the nation’s investment in cancer research · the nation’s investment in cancer research, the...

The National Cancer Institute

The Nation’sInvestment inCancer ResearchA Budget Proposal for Fiscal Year 2001

Prepared by the DirectorNational Cancer Institute

National Institutes of Health

Cancer surveillance – identifying and tracking trends in our national

cancer burden, and monitoring the factors that influence these

changes – is a crucial underpinning of our efforts to prevent and control cancer. For

example, increased surveillance efforts can help us understand and address the

unequal burden of cancer experienced by certain racial and ethnic groups in America.

To learn about NCI’s plans for all areas of cancer surveillance research, see page 92.

Surveillance

Scientists have learned

that all cells – normal,

precancerous, and cancerous – have

unique molecular features, or

“signatures.” Learn how we’re using

this knowledge to revolutionize cancer

detection and diagnosis – page 51.

Signatures

Using “molecular targets,” we may be able to design cancer treatments

that are “customized” for many patients, determine immediately

whether or not a particular treatment is working, and even decipher the mechanism of

action by which a drug works. See page 57 to find out what a “molecular target” is

and how they’re being used to transform cancer prevention and treatment.

Molecular Targets

“Functional imaging” allows us to monitor physiological processes (such

as blood flow, oxygen consumption, or glucose metabolism) and molecu-

lar activities as they take place in the body. Turn to page 45 to find out how NCI is

using new cancer imaging techniques to improve cancer detection, diagnosis, and

even treatment.

Imaging

Progress in cancer research is more dependent than ever on

the synergy of multidisciplinary teams of investigators and

on government, academia, and industry collaborations. See page 79 to learn how

NCI’s Centers, Networks, and Consortia are linking vital resources to address

important questions about human cancer.

Centers

Our current clinical trials infrastructure is insufficient to handle the

many exciting new drugs and drug combinations emerging from our

Nation’s laboratories. See page 84 to learn about NCI’s proposed National Clinical

Trials Program that will pave the way for us to translate new discoveries into

treatments and prevention strategies for patients.

Clinical Trials

Too few talented scientists are choosing careers in clinical oncology

research, and those that do are experiencing increasing clinical and

administrative pressures that impede their ability to conduct needed research.

To learn more about NCI’s plans to meet this challenge – and to attract much-needed

basic and population scientists to cancer research – turn to page 96.

Training

Every day, NCI’s

nationwide programs for

supporting cancer research are yielding

new discoveries, new prevention and

treatment approaches, and greater hope

for people with cancer and those at

risk – see page 12 for highlights of

recent progress.

Highlights of Progress

The late-20th

century revolution

in communications has had a profound

impact on how we convey important

information about cancer detection,

prevention, treatment, and risk to cancer

patients and those at risk. Turn to

page 69 to find out how.

Communications

Did you know that tobacco

use is directly responsible for

30 percent of all cancers, and 20 percent

of deaths overall, in the United States?

See page 62 to learn about the NCI’s

planned program of basic and behavioral

research on tobacco and addiction.

Tobacco

How do our genes interact

with environmental agents

in the development of cancer? NCI-

supported scientists are working to

find out. See page 38.

Genes

In our country,

some populations

are more severely affected by cancer

than others. NCI has an aggressive

program of research, training opportuni-

ties, and organizational structures dedi-

cated to understanding and addressing

the unequal burden of cancer in the

United States – see page 34.

Special Populations

NCI provides the Nation

with the most up-to-

date cancer information 24 hours a day,

7 days a week – through the Internet,

and by phone, fax, and more than 600

print and audiovisual materials. Turn to

page 33 to learn the many ways you can

access NCI’s information services.

Information

Colorectal cancer kills

more than 50,000

Americans each year. Find out how

NCI is fighting this disease – and

the screening tests that are currently

available – page 22.

ColorectalCancer

In Brief

The National Cancer Institute

The Nation’sInvestment inCancer ResearchA Budget Proposal for Fiscal Year 2001

The Nation’s Investment in Cancer Research, the Bypass Budget, communicates the needs andplans of the National Cancer Institute, in accordance with the legislative mandate containedwithin the National Cancer Act of 1971 [Public Law 92-218, Sec. 407 (b)(9)(A)]. Thisrequest is provided directly to the President in the Fall of each year as he formulates his budg-et request to the Congress for the entire Federal government and more specifically for cancerresearch. The amount exhibited within the President’s Budget may differ from the levelincluded in this document. The Congress, through the appropriations process, is empoweredto determine the final funding amount that is appropriated to the National Cancer Institute.

Prepared by the DirectorNational Cancer Institute

National Institutes of Health

2 The Nation’s Investment in Cancer Research

Director’s Message

A s we stand on the threshold of the 21st cen-tury, we can marvel at how far we’ve comein the battle against cancer. A hundred –

even fifty – years ago, cancer was a poorly under-stood disease that killed the great majority of peo-ple who had it. Today, we are learning more eachday about how cancer arises from a single cell thatbehaves abnormally, dividing uncontrollably andleading, eventually, to the development of atumor. We also are learning about the ways thatgenes, which direct the behavior of the cell, inter-act with a host of environmental agents to causecellular malfunction and disease. This basicknowledge about the nature of cancer is providingus with critical insights into how we can preventand detect cancer more effectively. And it is giv-ing us the opportunity to improve treatment byenabling us to design therapies that target themachinery of the cancer cell.

Thanks in large measure to the dedication andhard work of scientists across the Nation, we aremaking real progress against cancer. The rate ofnew cancer cases has been declining and the can-cer death rate falling. Powerful new technologiesare permitting us to detect and diagnose cancer atan earlier stage, before it has had the chance tospread. People with cancer are living longer, andwith a better quality of life, than ever before.

Truly, we are making progress, but for thosewho are touched by this disease, we are not mak-ing progress quickly enough. The declining inci-dence means little to Marisol, a mother of three,newly diagnosed with colon cancer, or to Paul, aretiree whose golden years are darkened bythe specter of chronic lymphoma, or to the

parents of sixteen-month-old Andrew, who isfighting for his life against an aggressive neuroblas-toma. The drop in the death rate is only anabstraction to the Corelli family, who were prema-turely robbed of a loving wife and mother by herovarian cancer, or to the classmates and friends ofMinh, a college student whose life was cut shortby leukemia. And although we have undoubtedlymade tremendous strides in our ability to detect,diagnose, and identify people at risk for cancer, wehave much to learn about what people who findthemselves at increased risk should do. Just askRachel, who at age 31 has learned that she has amarkedly increased risk of breast cancer due to analtered BRCA1 gene, and now faces the agonizingchoice of what preventive measures, if any, she isgoing to take to reduce her risk of this disease.

Furthermore, other recent trends threaten toovershadow our hard-won victories. The incidenceof melanoma, an aggressive skin cancer, has beenrising about three percent per year, although deathrates have remained constant, and incidence ratesfor non-Hodgkin’s lymphoma continue, inexplica-bly, to rise. In addition, adolescents are now smoking and using tobacco products – a major riskfactor for lung and other cancers – at a troublingrate, which may well reverse the currently fallingrates of lung cancer in coming years. Moreover,certain racial and ethnic groups continue to be disproportionately burdened by cancer.

How, then, can we continue to build on ourrecent accomplishments to make further much-needed progress against cancer? First, we must sustain the proven research programs that haveenabled us to pursue a path of scientific excellence

and discovery in cancer research. At the NationalCancer Institute (NCI), we have created an infra-structure that promotes discovery, worked withsome of the most innovative and productive scien-tists in the Nation, and initiated ground-breakingprograms that have yielded critical knowledge,improved patient care, saved lives, and improvedthe quality of life for many cancer survivors. Wemust continue to offer these programs our fullmeasure of support.

At the same time, we cannot hesitate to seizeextraordinary opportunities to further the progressbrought about by our previous research successes.Three years ago, we identified four areas of invest-ment that, if exploited, could produce dramaticprogress against cancer. We have made tremen-dous strides in each of these areas, and our progressis highlighted in this Bypass Budget, The Nation’sInvestment in Cancer Research: A Budget Proposalfor Fiscal Year 2001. In addition, we begin a newcycle of progress by identifying three additionalareas of extraordinary scientific opportunity.

Finally, we must ensure that the full promise of our research findings is realized by translatingour findings rapidly from the laboratory into prac-tical solutions that will benefit everyone. We out-line how this will happen in the “Challenge” section of this document for, indeed, our greatestchallenge is to assure that the insights of sciencebecome advances in medicine and public health.This Bypass Budget outlines the progress we havemade in this critical area and defines our plans for the future.

This document describes the budget we believewe will need to fund our research programs, aswell as the support we need to train the next gen-eration of top-flight scientists. It also details ouractivities in the crucial area of communicating up-to-date cancer information to patients, healthprofessionals, and people at risk for cancer. Finally,it serves as our central planning document, layingout clearly our funding priorities and presentingour vision of the Institute’s direction.

Since 1937, NCI has dedicated itself, throughits scientists and its resources, to the defeat of can-cer. We have made tremendous advances, but wecannot stop now. We must persevere in our work.For all of the Minhs and Marisols and Rachels andPauls of the Nation and the world, we must perse-vere. Through the careful application of researchand discovery, the 21st century can and will be theera in which cancer finally is conquered.

Richard D. Klausner, M.D.DirectorNational Cancer Institute

Director’s Message 3


Table of Contents

Director’s Message . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .62001 Bypass Budget Request . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10Highlights of Progress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12

Advances in Science and Technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12Charting Our Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16Foundations for Future Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17

The National Cancer Institute’s Role in Cancer Research . . . . . . . . . . . . . . . . . . .18Planning and Priority Setting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19Seeking Advice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20

How We Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24Supporting Our Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24

Extramural Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24Support for Extramural Clinical Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25Intramural Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .30Cancer Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31AIDS Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .32Training and Education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .32Other Research Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .33

Extraordinary Opportunities for Investment . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36Genes and the Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38Cancer Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45Defining the Signatures of Cancer Cells: Detection and Diagnosis . . . . . . . . . . . . . .51Molecular Targets of Prevention and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . .57Research on Tobacco and Tobacco-Related Cancers . . . . . . . . . . . . . . . . . . . . . . . . .62Cancer Communications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .69

NCI’s Challenge: Building the Capacity of the Future . . . . . . . . . . . . . . . . . . . . .74Investigator-Initiated Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .75Centers, Networks, and Consortia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .79National Clinical Trials Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .84Informatics and Information Flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .89Studying Emerging Trends in Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .92Training, Education, and Career Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . .96

FeaturesThe Consumer Advocate’s Role at NCI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21How We Spend Our Budget . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24Understanding Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27Informing Professionals and the Public: NCI’s Information Services . . . . . . . . . . . . .33Selecting Extraordinary Opportunities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37The Path to a New Cancer Drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .56

Spotlights on Research NCI’s Intramural Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .30Addressing the Unequal Burden of Cancer – Special Populations Research . . . . . . .34Malignant Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42How Can Spiral CT Improve Early Detection of Lung Cancers? . . . . . . . . . . . . . . . .48Viruses, Vinegar, and Vaccines – Preventing Cervical Cancer . . . . . . . . . . . . . . . . . .84

People’s StoriesColorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .64

Table of Contents 5


Executive Summary

T he National Cancer Institute (NCI) leadsthe Nation’s fight against cancer by support-ing and conducting ground-breaking research

in cancer biology, causation, prevention, detec-tion, treatment, and survivorship. Decades of workby NCI-supported scientists have produced realgains. The rate of new cancer cases declined anaverage of nearly one percent each year between1990 and 1996, while the cancer death rate fell,on average, 0.6 percent per year during that sameperiod. Powerful new technologies are enabling usto detect and diagnose more cancers at an earlierstage, before they have had the chance to spread.And many people with cancer are living longer,and with a better quality of life.

Even so, cancer continues to be a major healthproblem; for many Americans, it remains the mostfeared of diseases. In addition, the burden of can-cer falls disproportionately on certain racial, eth-nic and socioeconomic groups. Although we havemade real and lasting progress against the disease,it is critical that we continue to push forwardtoward our ultimate goal – preventing and curingall forms of cancer.

To more rapidly achieve our goal, NCI hasdeveloped the following plan:■ Sustain at full measure proven, productive

research programs.■ Seize extraordinary scientific opportunities made

possible by our previous research discoveries.■ Create and sustain mechanisms that build the

capacity to allow the scientific community toapply rapidly evolving discoveries and emergingtechnologies for the benefit of human health.

Sustain at full measure proven, productive research programs.In support of the entire community of cancerresearchers, NCI has developed an infrastructureof mechanisms, organizations, and networks thatlink scientists, facilities, and information. Eachyear, through NCI support, the efforts of thou-sands of scientists yield scientific advances in all of these areas.

In addition to basic, population, and clinicalresearch, we support investment in new researchprograms to address behavioral, surveillance, andcommunications research, as well as studies on theneeds of cancer patients and survivors. We alsosupport cancer centers, community-based clinicaloncology programs, training opportunities, andcommunications, education, and outreach pro-grams for both health professionals and the public.

Seize extraordinary scientific opportunities made possible by our previous research discoveries.In 1996, NCI began to systematically identifyareas in which focused efforts and increasedresources could help reduce the burden of cancer.Through this effort, we selected four areas ofextraordinary opportunity for investment: CancerGenetics; Imaging Technologies; Defining theSignatures of Cancer Cells; and Preclinical Models of Cancer. A plan of action addresses each of these opportunities.

This year, as we prepared to launch our “secondgeneration” of efforts, we carefully evaluated ourdirection and progress in each investment area. Wedetermined that the time is right to build on thefoundations we have laid over the past three years

Executive Summary 7

Summ

ary

in each “opportunity area” to resolvefundamental questions about cancer andimprove cancer detection, diagnosis,and treatment. From this evaluation, wealso determined that we should broadenour Cancer Genetics investment area toinclude the complex ways in whichgenes interplay with the environmentto affect cancer susceptibility and risk,and integrate our efforts in PreclinicalModels into the other investmentopportunities.

In this document, we identify threeadditional areas of extraordinary oppor-tunity: Molecular Targets of Preventionand Treatment, Research on Tobaccoand Tobacco-Related Cancers, andCancer Communications. Each of theseareas holds exceptional promise foradvancing our knowledge of cancer andfor helping patients and those at risk.

Genes and the EnvironmentThe new challenge in the study of can-cer causation is to apply the emergingtools of molecular genetics to under-stand how genes interact with an indi-vidual’s environment to cause cancer.These studies will, as a rule, involvelarge populations and will require newtypes of research mechanisms and strategies forinterdisciplinary collaboration. Despite the com-plexities involved, this endeavor holds great prom-ise in many ways: (1) Identifying cancer suscepti-bility genes with known pathways of action willpoint to previously unsuspected carcinogens.

(2) Studies of genetically susceptible groups willmake it easier to detect small variations in riskposed by certain types of environmental exposures.(3) Understanding how cancer susceptibility genesinteract with other genetic and environmental risk factors will result in new ways to diagnose,

All Sites

Female

Male

-3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0

Lung

Colon/Rectum

Breast (Female)

Prostate

Pancreas

Non-Hodgkin's Lymphoma

Leukemias

Stomach

Ovary

Brain & CNS

Annual Percent Change

Both

SEX

Annual Percent Change in U.S. Cancer Death Rates:Top 10 Sites 1990-1996By Sex, All Ages, All Races

prevent, and treat cancer. (4) Quantifying thecancer risks associated with susceptibility genesand environmental exposures will inform clinicaland public health strategies against cancer.

Cancer ImagingOver the last quarter century, refinements in imag-ing technology allow us to not only view struc-tures anatomically, but to visualize physiological,cellular, or molecular processes as they take placein living cells of the body. Parallel developmentsin image enhancement agents are improving ourability to capture changes in the biochemicalmakeup of cells and other living structures. Butdespite our progress, we still have important workto do before imaging technology can be applied toits fullest potential – when it will enable physi-cians to precisely locate precancerous and cancer-ous lesions, biologically characterize a lesion topredict how it is likely to respond to a specifictherapy, and directly monitor its response to treatment.

Defining the Signatures of Cancer Cells:Detection and Diagnosis All cells have unique, identifiable signatures –specific characteristics such as genes that areactive and proteins and other products that thecell manufactures. During the transformation of anormal cell to a cancer cell, the signature changes,signaling the presence of cancer. By identifyingand “reading” the signatures of cells, we can detectand diagnose cancer early, before it has had achance to spread and while it may still be easilycurable. We also can use the information from acancer cell’s signature to choose the most effectivetreatment, determine which cancers are likely tospread, and gain important insights into the etiol-ogy of the disease.

Molecular Targets of Prevention and TreatmentUntil recently, scientists working to discover effec-tive prevention and treatment agents have faced aformidable barrier: not knowing precisely whatcancer is. No longer is this the case. With the evolution of molecular biology and the emergenceof new technologies, we are gathering remarkableknowledge about the nature of a cancer cell andthe molecular changes that occur during a tumor’s

development. The extraordinary opportunitybefore us – to discover and exploit molecular tar-gets for cancer prevention and treatment – arisesfrom the convergence of scientific advances inseveral areas. A research emphasis on moleculartargets could lead to tremendous advances in pre-vention and treatment. Agents that target specificcharacteristics of a cancer cell presumably wouldleave normal cells alone and would be more effec-tive and less toxic than most traditionalchemotherapies. By understanding the changes,we can also develop targeted preventive drugs that can stop or even reverse those changes.

Research on Tobacco and Tobacco-Related CancersTobacco-related diseases are the most preventableand costly cause of death in the Nation, claiming450,000 lives each year. To respond to this ongo-ing crisis, we must comprehensively attack theproblem of tobacco use – expanding our under-standing of tobacco addiction, increasing ourknowledge of biological mechanisms underlyingtobacco-induced cancers, designing targetedapproaches that prevent people of all ages fromusing tobacco, developing ways to prevent theonset of tobacco-related cancers in smokers andformer smokers, and developing treatments fortobacco addiction and the cancers it causes. Wewill take full advantage of the constellation ofrecent scientific, public policy, social, educational,and legal advances that are providing an unparal-leled opportunity to address the tobacco problemin ways that integrate biological and psychosocialmodels of tobacco and addiction.

Cancer Communications Few health-related interventions have the poten-tial of interactive health communications toimprove health outcomes, decrease costs, andenhance consumer satisfaction. Indeed, effectivecommunication is central to cancer care, from primary prevention through survivorship. Today,we are in the midst of a communications revolu-tion. Experts are producing increasingly refinedapproaches to health communications, andchanges in the role and accessibility of informa-tion are altering health care practices, patient-physician relationships, and the way consumers


Executive Summary 9

Summ

ary

acquire and use information. We need to refineand apply these advances to improve outcomes incancer prevention, early detection, treatment, andsurvivorship.

Create and sustain mechanisms that build the capacity to allow the scientificcommunity to apply rapidly evolving discoveries and emerging technologiesfor the benefit of human health.We are learning more each day about the basicnature of cancer. Yet we are faced with the chal-lenge of converting these findings into advances incancer detection, prevention, and treatment. If thepace of discovery is like an eight-lane highway, ourcurrent ability to translate those discoveries intoclinical application is like a country road. Wherethe two meet, a bottleneck of good ideas occurs.Our challenge is to expand the country road to aneight-lane highway that moves discoveries swiftlyto their use in cancer care. Doing so means ensur-ing that sufficient technological resources, trainedscientists, and expanded infrastructures exist, andproviding the vision, creative environments, anddiverse resources needed to ensure there is nodelay between discovery and its application.

To respond to this challenge, we have identifiedsix key areas for investment: (1) Investigator-Initiated Research; (2) Centers, Networks, andConsortia; (3) National Clinical Trials Program;(4) Informatics and Information Flow; (5) Studying Emerging Trends in Cancer; and (6) Training, Education, and Career Development.Increased support in these areas will enable us tostrengthen our infrastructure and enable basic discovery to rapidly improve clinical practice.

Investigator-Initiated ResearchInvestigator-initiated research – research proposedand conducted by scientists in laboratories andclinics across the country and here at NCI – is thewellspring of scientific discovery. Discoveries madethrough investigator-initiated research are criticalto reducing the cancer burden. We must createmechanisms that link basic, clinical, and popula-tion-based researchers with state-of-the-artresources and technologies, promote collabora-tions among researchers inside and outside of can-cer research, and draw into cancer-related research

scientists from allied fields, such as chemistry, biology, physics, and mathematics. In addition, we must strive to expand our research portfolio to include a greater number of research proposalsthat may be somewhat riskier or highly specula-tive, or that pursue novel paths. We also mustconvert basic science discoveries into practical,affordable, and effective ways of restoring cancerpatients to health and preventing cancer through-out our population.

Centers, Networks, and ConsortiaWe find increasingly that multidisciplinary teamsare needed to solve the “big problems” in cancerresearch. It is necessary to create new kinds offunctional links among scientists in diverse disci-plines. We also need to ensure that theseresearchers have the tools and resources needed toconduct these essential studies. For these reasons,NCI must expand its Centers of Excellence andNCI-designated Cancer Centers programs anddevelop a variety of new research networks andconsortia.

National Clinical Trials ProgramThe research investment of the past decade hasbrought about a dramatic increase in the numberof new therapeutic and preventive agents showingenough promise to warrant testing in clinical trials.However, our present clinical trials system is failingto keep pace with these opportunities to improvecancer care. While fewer than three percent ofpatients with cancer participate in the clinical tri-als that define effective new prevention and treat-ment approaches, the number and complexity oftrials needed to determine the therapeutic roles ofthe new generation of agents continues to grow.Many more patient-volunteers are needed to helpestablish the benefits of new agents and new com-bination treatments, and a sufficient infrastructureto support these studies is needed.

Informatics and Information FlowThe power of computer-based communicationsand the World Wide Web are making possibleunprecedented research opportunities. Paper-basedresearch systems are giving way rapidly to integrat-ed systems that share information and knowledgeeffortlessly and enable new discoveries to be made

TABLE 1National Cancer Institute - 2001 Bypass Budget Request (dollars in thousands)

1999 2000 2001 2001 2001 Core,Operating President’s Core Core and Investments Budget Budget Request Investments & Challenge

Request Request

Research Project Grants (RPGs):Ongoing $983,129 $1,056,342 $1,166,993 $1,167,993 $1,172,793New (New and Renewal) 377,516 353,517 366,244 500,132 673,212Small Business Innovation Research 57,808 60,978 63,173 72,173 83,173Subtotal (RPG’s) 1,418,453 1,470,837 1,596,410 1,737,298 1,929,239

Intramural Research 488,884 487,144 506,630 518,380 549,180Cancer Centers 197,490 197,455 204,563 259,263 335,113Clinical Trials Infrastructure:

Cooperative Clinical Research 126,205 125,460 129,977 149,477 249,827Community Clinical Oncology

Program (CCOPs) 52,161 54,312 56,267 61,767 111,967Subtotal (Trials Infrastructure) 178,366 179,772 186,244 211,244 361,794

Training and Education 112,123 117,256 122,097 134,097 173,172Research Support Contracts 275,087 298,569 309,519 399,680 490,165Cancer Control Management

and Support 89,882 82,640 85,946 94,946 97,246Research Management and Support 108,965 110,065 114,468 129,468 148,468Other 26,866 29,181 32,124 50,624 50,624

Total NCI $2,896,116 $2,972,919 $3,158,000 $3,538,000 $4,135,000

Cancer Control included above $301,259 $312,719 $334,278 $462,778 $565,578

at the researcher’s desk, not just in the lab. NCImust construct a new information architecture for the cancer research process. This CancerInformatics Infrastructure will help speed the discovery process, translate the best discoveriesinto clinical trials, and transform cancer carethrough more effective and efficient informationexchanges. By drastically reducing the time andeffort required to make new discoveries or applyexisting discoveries, this revolution will result in adramatic acceleration of progress against cancer.

Studying Emerging Trends in CancerAppropriate decision making in science and in public health depends on accurate, reliableinformation about the incidence and impact of

disease. NCI uses data from the Surveillance,Epidemiology, and End Results cancer registry program to identify and study trends, track theimpact of cancer on the general population, andprovide information to help researchers find outwhy certain populations are affected by cancermore severely than others. However, recentchanges in health care financing and delivery, therevolution in informatics and computer program-ming technology, and the social and culturaldiversity of our country present new challengesand opportunities in surveillance research. Weneed to expand our data collection to include pat-terns of cancer care, as well as treatment and qual-ity of life outcomes. In addition, new investmentsare required to find tools that will improve the


precision and expand the reach of cancer surveil-lance. NCI’s surveillance efforts should encompassa broader spectrum of the racial, ethnic, socioeco-nomic, and cultural diversity of our country.Greater efforts are needed to disseminate theresults of NCI’s surveillance research, and, finally,we must create the training programs to preparethe next generation of surveillance researchers.

Training, Education, and Career DevelopmentCurrently, too few promising individuals arechoosing careers in cancer research. Those who doare faced with a field of increasing complexity, yetthey have decreasing amounts of time reservedfrom clinical and administrative responsibilities toconduct important research, mentor new scien-

tists, or obtain necessary continuing training forthemselves. New ways of educating, training, anddeveloping scientists are necessary to ensure thattechnology advances are integrated rapidly intothe cancer research enterprise and that scientistsare prepared to work together in team settings tounravel the complex factors contributing tohuman cancer.

To strengthen the infrastructure for discoverythat supports all of our research efforts, continueprogress in pursuing our ExtraordinaryOpportunities for Investment, and speed the flow of discovery into application, the NationalCancer Institute requests the funding presented in Tables 1 and 2.

Executive Summary 11

Summ

ary

2000 President’s 2001 2001 2001 2001Budget Core Investment Challenge Total

Research Project Grants $1,470,837 $125,573 $143,889 $188,940 $1,929,239Intramural Research 487,144 19,486 11,750 30,800 549,180Cancer Centers 197,455 7,108 54,700 75,850 335,113Clinical Trials Infrastructure 179,772 6,472 25,000 150,550 361,794Training and Education 117,256 4,841 12,000 39,075 173,172Research Support Contracts 298,569 10,950 90,161 90,485 490,165Cancer Control

Management and Support 82,640 3,306 9,000 2,300 97,246Research Management

and Support 110,065 4,403 15,000 19,000 148,468Other 29,181 2,943 18,500 50,624Total $2,972,919 $185,081 $380,000 $ 597,000 $4,135,000

Challenge14%

Investment9%

Core5% 2000

President’sBudget72%

TABLE 22000 Base Amount with 2001 Increases (dollars in thousands)


Highlights of Progress

S cientific progress may sometimes seem to moveforward at a frustrating pace. Because advances

in basic research, prevention, and treatment areincremental, it often takes years to see the cumu-lative effects of our efforts on populations at risk,patient survival, and improved quality of life.Moving from an insight to a tested, successfulintervention in people takes time, and there willalways be a lag between our investment in devel-oping a solid knowledge base and the payoff for aperson with cancer or one at risk for the disease.Yet every day, thanks to the dedicated efforts ofcancer researchers and clinicians, we are growingcloser to our goal of overcoming cancer.

In these final years of the twentieth century, wehave seen an explosion of progress against cancer.We have witnessed a number of importantadvances culminating from many years of inten-sive effort. We have begun to gather significantinformation from programs launched only two orthree years ago. And with our recent fundingincrease, we have been able to launch innovativenew programs that will have far-reaching effectsinto the next century. The following highlights of recent progress demonstrate how far we havecome against cancer, and offer a glimpse of what is to come as we continue to build on our success-es to conquer cancer in a future that is no longerso distant.

ADVANCES IN SCIENCE ANDTECHNOLOGY

Preventing Cancer/Cancer Control

Finding effective ways to prevent cancer has long been a central focus for NCI and cancerresearchers. Prevention can take many forms, fromsmoking cessation and other behavioral changes

to vaccines or antimicrobial agents against cancer-causing infections. Importantly, our increasingknowledge of cancer biology is enabling us toidentify agents – both natural and man-made –that may prevent cancer by interfering with thebiological processes underlying cancer develop-ment. In fact, more than 50 compounds currentlyare being investigated for their potential efficacyas cancer preventives.

Closely related to cancer prevention, cancercontrol encompasses research on the many diverseaspects of translating proven technologies andtested methodologies into routine practice in thecommunity. For example, cancer control researchmay focus on identifying new ways to help peoplestop smoking, or to encourage people to adopt ahealthier diet, or to communicate health risks tocertain population groups. NCI’s commitment toground-breaking cancer control research is evidenced by its new Extraordinary Opportunitiesin Research on Tobacco and Tobacco-RelatedCancers (see page 62) and CancerCommunications (see page 69).■ In recent results from the Breast Cancer

Prevention Trial, tamoxifen, a drug long usedfor breast cancer treatment, led to a 49 percentreduction in the incidence of primary breastcancer during the treatment period in womenat high risk for the disease. This outcome marksan important landmark in this line of research.However, because tamoxifen may have seriouslong-term side effects, NCI recently beganrecruiting volunteers to participate in a studyto determine whether the drug raloxifene is aseffective in reducing breast cancer risk astamoxifen, but with fewer undesirable sideeffects. The Study of Tamoxifen and Raloxifene(STAR) will compare the effectiveness and thelong-term safety of these two medications inwomen at increased risk for breast cancer.

Highlights of Progress 13

Highlights

■ Some women who are at high risk of breastcancer make the difficult decision to have bothbreasts surgically removed, a procedure knownas bilateral prophylactic mastectomy (PM). Ina recent retrospective study of 639 women witha family history of breast cancer who hadundergone the procedure, PM was associatedwith a 90 percent reduction in the incidenceof breast cancer. And in another study, pro-phylactic oophorectomy – surgical removal ofthe ovaries – was found to reduce breast can-cer risk by about 40 percent for women withcancer-predisposing BRCA1 mutations.

■ The sale of cigars in the U.S. has been increas-ing since 1993, but until recently little wasknown about their health effects. However,researchers have found that compared withnonsmokers, cigar smokers were at increasedrisk of lung and upper aerodigestive tract cancer, as well as heart and lung disease. Theseimportant findings highlight the need for prevention efforts aimed at cigar smokers.

■ Because tobacco use is responsible for over 30 percent of all cancers, research on moreeffective smoking prevention and cessationapproaches is a cornerstone of the Institute’scancer control efforts. Two recent studies haveadded to our knowledge. In one, researchersfound that the passage of a comprehensiveordinance ensuring merchant compliance withtobacco age-of-sale laws in seven communitiessignificantly reduced daily smoking amongeighth, ninth, and tenth graders, compared tocommunities without such an ordinance. In theother, women who participated in an exerciseprogram concurrently with a behavioral smok-ing cessation program had a higher success ratethan women who underwent the behavioralprogram but did not exercise. In addition,women in the exercise program had gained lessweight by the end of the program.

Detecting Cancer

New technologies that will enable us to detect anddiagnose cancer early, before it has had the chanceto spread, are on the horizon. Imaging devices andmodalities are being developed and tested thatallow us to visualize the cell with greater precisionthan ever before (see page 45). In addition, new methods of reading the signatures of cells (see page 51) are enabling us to identify the subtledifferences between normal and cancer cells, andare leading us to the day when only a simple blood test is needed to detect cancer anywhere in the body. ■ Current methods for the non-invasive detec-

tion of small tumors are limited in their abilityto distinguish small areas of abnormal cells fromlarger surrounding areas of normal tissue.Researchers have developed a new method tomore precisely image tumor cells. They injectedtumor-bearing mice with a unique imagingagent composed of near-infrared fluorescenceimaging probes coupled with a novel copolymerthat moves efficiently into tumor cells. Whenthe agent was absorbed into the cancer cells,enzymes within the cells “activated” the agentand caused it to fluoresce. The fluorescencecould then be detected non-invasively. Theagent was not activated in non-tumor cells.Using this technique, investigators were able toimage tumors smaller than three-tenths of amillimeter in diameter. Although this tech-nique is in the early stages of development, itshows great promise for the detection of verysmall tumors.

Treatment Advances

As recently as thirty years ago, when legislationlaunched the National Cancer Program, the ideaof curing cancer seemed a remote ideal. This idealis now a reality for a growing number of cancersand within our grasp for many others. Today, usinginsights gleaned from discoveries about cancerbiology, we are learning to tailor treatments for aspecific cancer in a specific individual, to optimizethe effectiveness of traditional treatments, and totarget treatments to the cellular machinery of specific tumors. Our great hope is that targetedtreatments will prove to be more effective and less toxic than our current approaches.■ An exciting approach to cancer treatment is

immunotherapy, or treatments in which thepatient’s own immune system is coaxed to rec-ognize and eradicate cancer cells. One targetedimmunotherapeutic approach that recently hasmet with exciting success involves the use ofmonoclonal antibodies, proteins derived fromcells found in the body’s own immune system,that attach to the surfaces of cancer cells anddeliver a deadly substance directly to them.Based on clinical trial results, two monoclonalantibodies recently have been approved for usein cancer treatment: Rituxan® for B-cell lym-phoma, and Herceptin® for metastatic breastcancer. Clinical trials are underway to deter-mine whether these agents may be used orenhanced to combat other types of cancer.Another type of immunotherapy involves cancer treatment vaccines. NCI is sponsoringmore than 70 vaccine therapy trials, includingstudies on using vaccines to treat melanomaand cancers of the breast, prostate, cervix, kidney, pancreas, and ovary.

■ Another evolving treatment approach targetsthe process of angiogenesis. Presently, about 20 angiogenesis inhibitors – agents that blockthe development of tumor-nourishing newblood vessels – are being tested in human trials,and others showing promise in animal studieswill soon enter human trials. For example, thedrug thalidomide, long banned from medicalpractice for causing severe birth defects in chil-

dren born to mothers who took the drug duringpregnancy, has been shown to be a potentangiogenesis inhibitor. In a small trial ofprostate cancer patients, thalidomide caused adecline in the biomarker PSA in 68 percent ofthe patients – an indicator that thalidomidecould be effective against prostate cancer. In aseparate study, thalidomide was shown to inducetumor shrinkage in 45 to 50 percent ofpatients with AIDS-related Kaposi’s sarcoma.

■ Our success in treating childhood cancers, particularly leukemia, was the first proof thatcancer could be treated and cured. Years of trials focused on improving chemotherapies forchildren with acute lymphocytic leukemia(ALL) resulted in our current ability to cure 75 to 80 percent of children diagnosed withthis disease. For 20 percent of children withALL, however, our treatments were ineffectiveand the children fared poorly. Results of a newtrial using a modified chemotherapy regimenhave shown a 70 percent drop in the rate oftreatment failure in these high-risk children.

■ Five clinical trials involving women with local-ly and regionally advanced cervical cancershowed that when cisplatin-based chemothera-py was given concurrently with radiation thera-py, the risk of cervical cancer death wasreduced by 30 percent. Based on these defini-tive results, NCI strongly urges that physiciansconsider adding chemotherapy to the treatmentof women who require radiation therapy forcervical cancer.

■ Results from clinical trials under the long-run-ning National Surgical Breast and BowelProject show that adding tamoxifen to lumpec-tomy and radiotherapy in women with ductalcarcinoma in situ (DCIS) reduces the risk ofsubsequent invasive breast cancer. Takentogether with results of an earlier trial, thesefindings suggest that lumpectomy, breast irra-diation, and tamoxifen can safely substitutefor mastectomy in the treatment of DCIS. Inaddition, women with DCIS treated withlumpectomy alone have a significantlyincreased risk of eventually developing breastcancer, and thus should be considered a high-


risk group that merits consideration for preven-tive treatment with tamoxifen.

■ 3-Dimensional Conformal Radiation Therapy(3DCRT) is a new approach that employssophisticated computer technology to fit thetreatment field more tightly to the tumor, inthree dimensions, than was possible using con-ventional techniques. Researchers used 3DCRTto treat patients with advanced prostate cancerand found that they could safely give higherdoses of radiation to the tumor and increasethe probability of local tumor control. Usingan advanced form of 3DCRT, Intensity-Modulated Radiotherapy, significantlydecreased treatment complications among the same group of men.

Understanding Cancer and its Causes

With the knowledge that cancer is a genetic disease, we now look to our genes for clues abouthow the disease develops and progresses in thebody. As a first step in this search, we are workingto identify the mutated genes that give rise to can-cer. A second – and equally important – step is todetermine how these genetic changes contributeto cancer. ■ Newly developed technologies now enable us

to develop mouse models of human cancers byaltering or inactivating mouse genes and intro-ducing into mice the same mutations that occurin humans. Using such models, cancerresearchers recently identified a gene, Smad3,that plays a role in the development of colorec-tal tumors. Researchers also elucidated the roleof the normally functioning PTEN gene, whosemutated form is found in a large percentage ofprostate, brain, breast, endometrial, skin, andkidney tumors. These discoveries will pave theway for further study of the biological changesthat underlie cancer, and may even lead to newpreventive or treatment interventions.

■ As noted above, a number of angiogenesisinhibitors are now being tested in clinical trials.This is a result of our successful efforts tountangle the mysteries of cancer biology, and

the subsequent growth of our understanding ofangiogenesis. The prevailing view holds thatmost tumors originate without blood vessels,and only induce angiogenesis once they grow toa specific size. Important new evidence suggests,however, that some tumors initially coopt exist-ing vessels to form a well-vascularized tumor,but the coopted vessels quickly regress and thetumor loses many of its cells. Ultimately, theremaining cells are rescued by angiogenesis –through the collaboration of the angiopoietin-2(Ang-2) and vascular endothelial growth factor(VEGF) proteins – and the tumor continues togrow. These findings suggest that inhibitingVEGF, a powerful angiogenesis stimulator, canimpede tumor growth by preventing thisprocess and perhaps promoting the regression offragile new tumor vessels. And Ang-2, appar-ently the earliest marker of blood vessels dis-turbed by tumor cells, may prove useful for earlydetection and as a treatment target.

■ Newly developed tools are helping scientistsperform large-scale analyses of the vast humangenome to genetically characterize tumors,information that can help to explain whypatients diagnosed with the same cancer differdramatically in their responses to treatment,and in their prognoses. For example, theLymphochip, a computer chip-like device withDNA from more than 15,000 genes importantto both the immune system and lymphoid can-cers, is enabling researchers to study the genesactive in non-Hodgkin’s lymphoma, a cancerrising in incidence. The lymphochip promisesto be a useful tool for detecting lymphomasearly, analyzing risk, and selecting targetedtreatments. A similar device, an affinity-basedbiochip, was developed by NCI and FDA inves-tigators to generate biomarker profiles of normal, precancerous, cancer, and metastaticcells from esophageal, prostate, colon, andliver tissues. Biomarker pattern profiles revealchanges in protein expression as tissue cellstransition from normal, to premalignant, toinvasive cancer; this new technology could beextremely useful in the discovery of disease-


Highlights

related proteins, therapeutic assessment, andtreatment toxicity monitoring.

■ Our research on cancer also has revealed thatelements in our environment play a significantrole in cancer’s development. Tobacco use, forexample, accounts for about one third of cancerdeaths in this country. Recently, several groupsof scientists found intriguing evidence of a possible genetic predisposition for smoking,accounting for some peoples’ inclination tosmoke or inability to stop. Greater knowledgeof how these genes influence smoking promisesto provide important clues about how somepeople become addicted to nicotine, and howwe can effectively help smokers stop smoking.

CHARTING OUR FUTURENCI’s mission to conquer cancer – to reduce andfinally remove the burden of this disease on pres-ent and future generations – is the driving forcebehind the Institute’s diverse research programsand activities. Planning for a future free from thefear of cancer requires that we leverage the valueof our growing body of knowledge about cancer,and that we challenge the research community togo beyond its customary practices to achieve ourultimate objective. We must develop initiatives,programs, and new partnerships to most effectivelyuse new discoveries, exploit scientific opportuni-ties, and apply emerging technologies to prevent,detect, treat, and control cancer.

NCI has spent much time and effort developingand supporting an infrastructure that sustains theresearch programs that today are enabling us topursue a path of scientific excellence and discoveryin cancer research. In tandem, we have establisheda tradition of seeking better ways to inform theprocess of identifying needs and opportunities inthe cancer field, setting priorities, and implement-ing decisions and recommendations that lead tonew or improved research initiatives and programs.■ NCI recently assembled Progress Review

Groups composed of researchers, health profes-sionals, industry representatives, and lay advo-

cates to assess the state of our knowledge, iden-tify scientific opportunity and need, and chart acourse for future study in two high priorityresearch areas: prostate cancer and breast can-cer. NCI now is using the Groups’ recommen-dations to help set a national research agendain these areas. A colorectal cancer PRG isplanned for this year.

■ Working Groups and Implementation Groupsalso play a critical role in charting the course of research. For example, one such group, theTobacco Research Implementation Group(TRIG), was charged with establishing NCI’stobacco-related cancer research priorities forthe next five to seven years. Another group,the Surveillance Implementation Group(SIG), was charged with identifying prioritycancer surveillance research areas and optimalstrategies for using surveillance measures toadvance our knowledge of cancer.

■ NCI also has engaged groups of experts outsidethe Institute to perform in-depth evaluations of various programs within the Instituteand recommend ways to enhance the structureand function of the programs under study. For example, a recent review of theDevelopmental Therapeutics Program (DTP),NCI’s organizational focal point for new cancertreatment development, highlighted the needfor DTP to respond to the needs of rapidlychanging science and technology. The reviewgroup emphasized that new basic knowledgeand technologies must be integrated into theprocess of discovering and developing anti-can-cer drugs to allow DTP to meet the challengeof drug development in the next decade. Inaddition, recommendations from a review ofthe clinical trials program resulted in a recent-ly launched restructuring of our treatment clini-cal trials program. In this first major systemreform in forty years, we hope to ensure thebest science, improve physician and patientaccess to trials, and enhance program efficiencyand effectiveness.


FOUNDATIONS FOR FUTUREDISCOVERY

To conquer cancer, NCI must not only pursue newknowledge, but ensure that we have the trainedscientists, the technologies, and the necessaryinfrastructures poised to take our considerableknowledge about cancer and apply it to reduce theburden of suffering it causes. These are the foun-dations for discovery that support our continuedsuccesses, and they must be continually evaluated,strengthened, and expanded to enable us to fullyseize opportunities for progress. Important compo-nents of our foundations for discovery werelaunched or enhanced this year.■ The Cancer Genome Anatomy Project

(CGAP) was established by NCI two years agoto systematically identify the gene expressionpatterns that characterize human cancer. Wehave made important progress in this project.For example, we have catalogued approximately70,000 genes that are expressed in cancers andtheir precursors; of these, about 30,000 are previously unknown genes.

■ Through the Director’s Challenge: Toward aMolecular Classification of Tumors, NCI ischallenging the scientific community to pursueresearch harnessing the power of molecularanalysis to create a system for classifying tumorsaccording to their molecular profiles. This“Director’s Challenge” is intended to lay thegroundwork, over a five year period, for chang-ing our tumor classification system from onebased on visual characteristics to one based onmolecular characteristics. This information willfundamentally change our approach to diagnos-ing cancer, to choosing cancer therapy, and topredicting a patient’s outcome.

■ Over the past two years, CGAP also hasenabled the discovery of hundreds of potentialmarkers for cancer, bringing us closer to thepossibility of sensitive, accurate, and predictivetests for early cancer detection. With new fundsreceived this year, the Institute has establishedthe Early Detection Research Network(EDRN), a national scientific consortium ofacademic and industrial researchers who will

work toward rapidly developing and testingsuch markers for cancer. Ultimately, thisresearch is expected to yield simple tests fordetecting all types of cancers that can be performed on easily sampled body fluids.

■ To ensure that we not only fill but expand thepipeline to new cancer prevention and treat-ment approaches, NCI recently initiated theRapid Access to Intervention Development(RAID) program. Through this program, wewill be able to identify promising proposals andfund the rapid movement of new therapeuticreagents from the laboratory to the clinic.Because of its initial success, we have decidedto expand RAID and to launch RAPID, a program offering the same process for potentialpreventive agents.

■ Americans increasingly are turning to comple-mentary and alternative medicine (CAM) fortreatment and supportive care of numerous diseases and conditions, including cancer. Inresponse to this growing trend, NCI has estab-lished the Office of Cancer Complementaryand Alternative Medicine, which seeks to pro-mote and support research in the various disci-plines and modalities associated with CAM asthey relate to cancer diagnosis, prevention, andtreatment and the management of cancerpatients.

■ Because cancer strikes certain racial and ethnicminority groups disproportionately, NCI recent-ly launched the Special Populations Networksfor Cancer Awareness Research and Training.The Networks will fund a diverse group ofresearch projects aimed at improving cancerprevention and control in minority and under-served communities. Principal goals of the newNetworks will be to develop and maintain part-nerships between scientific researchers andcommunity leaders in an expanded range ofminority and underserved populations, developand test community cancer awareness activities,support minority enrollment in clinical trials,and encourage minority scientists to participatein cancer research. Initial awards under the program will be made in March 2000.


Highlights


The National Cancer Institute’s Role in Cancer Research

T he National Cancer Institute (NCI) ischarged to lead our Nation’s research effortto conquer this disease in all its forms. As

the Federal focal point for cancer research in thiscountry, NCI conducts, coordinates, and fundscancer research, and provides vision and leader-ship for the cancer research community. Each day,across the United States and around the world,thousands of NCI-funded researchers and clini-cians are joined together by a common goal – theyare working toward a day when cancers are anuncommon and easily treatable set of diseases.

NCI supports this vital work through researchprograms that seek answers to the many remainingquestions about how best to prevent and treat can-cer. Pursuing these answers can take one of twointerrelated and complementary paths – studyingthe cancer cell itself to uncover biological processesbroadly applicable to all cancers, or studying oneof the more than 100 specific types of cancer.Though these research approaches appear to bedivergent, they are inextricably linked, and infact, most fruitful when there is extensive inter-play and cross-fertilization between them. As wedevelop an understanding of biological processescommon to many tumor types, we gain newknowledge that can be applied to cancer-specificresearch, and as we make discoveries about a spe-cific cancer, new questions about themes commonto all cancers are prompted.

Research on common biological processes,broadly applicable research, focuses on uncoveringfeatures that are common to all normal, precan-cerous, and cancerous cells. Basic research hastaught us that one or more cellular mechanisms –cell growth, cell death, invasion, metastasis, avoid-ance of immune system attacks, and the accumula-

tion of genetic changes that lead to cancer – are,in different combinations, responsible for mostcancers. In addition to providing us with newinsights into mechanisms common to cancer cells,basic research helps us to better distinguish onecancer from another based on molecular charac-teristics. Distinguishing cancers according to theirmolecular characteristics is becoming as importantas the traditional way of defining a cancer by thesite in which it arose.

Basic research is not abstract; rather, it is thegeneration of essential knowledge that can beapplied directly to each specific type of cancerthat people experience. For example, scientistsstudying the process of angiogenesis, the formationof new blood vessels that tumor cells exploit togain nutrients and growth factors, identified sever-al potential anti-angiogenesis agents. The discov-ery of these agents, which may prove effective incombating a variety of human cancers, might nothave occurred without broad research into thebasic biological processes common to all cancers.

Disease-specific research is aimed at uncoveringthe biological characteristics that are unique toeach specific cancer, such as breast or prostatecancer. Here the goals are to design effectivemethods of preventing, detecting, diagnosing, andtreating the cancer, and to address disease-specificsurvivorship issues. Disease-specific research alsoyields information that applies to many diversecancers. For example, researchers studying thevery rare childhood cancer of the eye calledretinoblastoma discovered a gene, Rb, that whenaltered is the trigger that leads to retinoblastomadevelopment. Scientists continued to study Rb anddiscovered the interconnected molecular machin-ery of a cellular circuit called the Rb pathway.

This pathway is found in all cells, not just thosethat give rise to retinoblastoma, and at least onecomponent of the Rb pathway is altered in everyhuman cancer. Thus, a discovery unique toretinoblastoma eventually led to an understandingof a pathway that is found in all cells.

Our efforts to answer the key questions of can-cer research through either broadly applicableresearch or disease-specific research involves fourclasses of investigation – laboratory, clinical, popu-lation, and translational. Laboratory researchfocuses on the biology of cancer, the fun-damental properties of cancer-causingagents and processes, and the body’sdefense against and response to cancer. Inthe clinic, research is carried out on can-cer prevention, diagnosis, treatment, andrehabilitation. Population research focuseson the causes, risks, predisposition, inci-dence, and behavioral aspects of cancer.Finally, translational research buildsbridges and intersections between andamong the classes of research. It facilitatesthe movement of discoveries from labora-tory and population research into the clinic and,conversely, provides a way for clinical insights tohelp direct laboratory and population-basedresearch. This flow of information among the lab-oratory, the clinic, and the community helps todrive research in new directions.

How do we know what questions to pursue inthese four classes of research, be they broadlyapplicable or disease-specific? The keys to estab-lishing this scientific direction are our planningand priority-setting processes; program review,progress review, and implementation efforts; and

input we receive from our advisory groups and thecommunity.

PLANNING AND PRIORITY SETTING

Planning – identifying needs and opportunities, set-ting priorities, implementing decisions and recom-mendations, and making sure that a reliable infra-structure supports all of our initiatives – is an inte-gral part of all NCI activities. Setting NCI’s fundingpriorities is a complex and dynamic process driven

by several principles. We must support thefull range of research activities necessary toconquer cancer; therefore, we strive for abalanced portfolio of research in behavior,epidemiology, control, prevention, detec-tion, diagnosis, and treatment, as well assurvivorship, rehabilitation, and end of lifeissues. This balance must include attentionto the spectrum of distinct diseases we col-lectively refer to as cancer and the variouspopulations that experience these diseasesdifferently. We must not only balancethese pieces of the cancer research enter-

prise but link them through translational research.In addition, we must rely on our diverse constituen-cies to help us identify new opportunities, gaps, andbarriers to progress, and to help us create new pro-grams and improve existing ones.

Program ReviewsNCI supports research through a variety of mechanisms, many of which provide funds tailoredto specific research processes. As part of an ongo-ing process of review and revitalization, NCI hasinstituted a series of external reviews to guide us

NCI’s Role in Cancer Research 19

NCI’s Role

Program Review

reports can be

found at

http://deainfo.

nci.nih.gov/

advisory/

boards.htm

http://deainfo.nci.nih.gov/advisory/boards.htm

in strengthening our major research support pro-grams. In the past few years, we have completedin-depth reviews of several programs: CancerCenters, Cancer Control, Clinical Trials, CancerPrevention, and the Developmental TherapeuticsProgram.

Progress ReviewsOne way NCI seeks the advice of experts isthrough Progress Review Groups (PRGs) com-posed of prominent members of the scientific,medical, and advocacy communities whoknow the state of the science intimatelyand can provide a thoughtful, consideredassessment of our portfolio and recom-mend activities that will speed ourprogress. The overall goal of the PRGs isto provide recommendations for a nation-al cancer research agenda. PRGs meetregularly over a period of months toreview an NCI-prepared analysis of theInstitute’s current research program,review recommendations from theresearch and advocacy communities,define and prioritize unaddressed scientif-ic opportunities that should be pursued,and to develop a plan of action for the research area.

In the past year, PRGs in Breast and ProstateCancer completed their assessments of ourresearch programs and we have begunconsidering and implementing their rec-ommendations. A PRG in ColorectalCancer is planned for 1999.

Implementing RecommendationsProgram reviews, progress reviews, andother assessment and advisory activitiesconducted at NCI generate not onlyinsights, but also recommendations con-cerning how best to organize a program orpursue a field of research. Implementingthese recommendations is key to success-ful planning, as planning alone does notbring about change. To implement changes, wehave formed groups of outside scientists and NCIstaff that grapple with the redesign of programsand development of new initiatives that are rec-

ommended by the Program Review Groups,Progress Review Groups, and extraordinary oppor-tunity Working Groups. Ongoing ImplementationGroups include those focused on Clinical Trials,Prevention, Surveillance, Diagnostics, TobaccoResearch, and Early Detection.

SEEKING ADVICE

To ensure the wise use of resources to meet thegoals of the National Cancer Program,NCI actively seeks out expert advice froma variety of advisory bodies both withinand outside the Institute.

National Cancer Advisory Board NCI’s principal advisory body is thePresidentially appointed National CancerAdvisory Board (NCAB). The NCAB,with a membership including scientificexperts and advocates, advises NCI’sDirector on issues related to the entireNational Cancer Program and provides a second level of review for grant applications referred to NCI.

Board of Scientific Counselors The Board of Scientific Counselors (BSC) advisesthe Institute leadership on the progress and future

direction of NCI’s Intramural ResearchProgram. These scientific experts from out-side NCI, along with consumer advocacycommunity representatives evaluate theperformance and productivity of NCI staffscientists through periodic site visits tointramural laboratories, and evaluate andadvise on the course of each Division’s programs.

Board of Scientific Advisors With the BSC, the Board of ScientificAdvisors (BSA) represents the scientificcommunity’s voice in the science NCI

conducts and supports. The BSA, composed of dis-tinguished scientists from outside NCI and repre-sentatives from the consumer advocacy communi-ty, advises the NCI leadership on the progress and


The Breast

Cancer Progress

Review report

can be found at:

http://wwwosp.

nci.nih.gov/

planning/prg/

bprgtableof

contents.htm

The Prostate

Cancer Progress

Review report

can be

found at:

http://wwwosp.

nci.nih.gov/

planning/prg/

toc.htm

http://wwwosp.nci.nih.gov/planning/prg/bprgtableofcontents.htm

http://wwwosp.nci.nih.gov/planning/prg/toc.htm

future direction of the Institute’s ExtramuralResearch Program. The BSA evaluates Institute-awarded grants, cooperative agreements, and con-tracts, and reviews ideas for new research solicita-tions to ensure that the concepts are meritoriousand consistent with the Institute’s goals.

NCI Executive Committee The NCI Executive Committee, which includesNCI Division directors and other key advisors tothe Director, meets regularly to make major policyand operating decisions for the Institute.

Director’s Consumer Liaison GroupEstablished in 1997, this first all-consumer advocate advisory committee at NCI consists of 15 consumer advocates who represent thediverse face of consumer advocacy across the U.S. Its purposes are to:■ Serve as a primary forum for discussing issues

and concerns and exchanging viewpointsimportant to the broad development of NCI program and research priorities.

■ Help develop and establish processes, mechanisms, and criteria for identifying appropriate consumer advocates to serve on NCI program and policy committees.

■ Establish and maintain strong collaborationsbetween NCI and the advocacy community.

Community InputInput from the community is very important toNCI. So that we can better understand the needsof cancer patients, those at risk for cancer, andinterested parties in the lay community, NCIestablished the Office of Liaison Activities(OLA). As NCI’s public liaison office, OLA fos-ters and enhances communication with this com-munity and addresses the concerns of Congressand the community about how NCI sets researchpriorities. OLA maintains ongoing communica-tions and information exchange between thenational cancer advocacy organizations and NCI,

encourages input and feedback from these organi-zations, and cooperates and collaborates withthese groups in areas of mutual interest. TheOffice supports the Division of ExtramuralActivities in expanding representation of con-sumer advocates on NCI peer review panels andcoordinates and supports the Director’s ConsumerLiaison Group. OLA also builds relationships withprofessional societies and other Federal agencies,and provides input and perspective to NCI oncomplex issues relevant to cancer patients and the public.

The Consumer Advocate’s Role at NCI

Our work aims to support people with cancer, their fami-lies, their friends, and those at risk for developing the dis-ease. We recognize this diverse community of peopleaffected by cancer as key stakeholders in our quest to con-quer the disease, and we are including those who repre-sent the voices of this community – consumer advocates –in virtually all levels of NCI’s decision making processes.Consumer advocates as members of NCI advisory commit-tees and planning/oversight groups, play a vital role inprogram planning and implementation and help to set pri-orities and research agendas.

These advocates, often cancer survivors, provide thepatient’s view on a wide range of issues including those ofspecial concern to minority and medically underservedpopulations. In addition, they often are advocate leaderswho have a broad view of the cancer problem and areversed in the science. In 1999, NCI consumer advocatesparticipated in the review of grant and contract applica-tions and in site visits and review committees. They alsoprovided ideas and recommendations for developing anddisseminating templates for new, easier to understandinformed consent documents.

NCI’s Director’s Consumer Liaison Group and our otherconsumer participation efforts, both coordinated throughour Office of Liaison Activities, have served as models forthe National Institutes of Health (NIH) community.


NCI’s Role


I turned 50 this year. There’s no history of colorectal cancer in myfamily, but my doctor said it’s timeto begin screening for the disease.Frankly, I found the idea of itembarrassing and, well...disgusting.

Almost 130,000 people will be diag-nosed with cancer of the colon orrectum this year, and some 56,000will lose their lives to these cancers.Ninety percent of cases occur inpeople older than age 50, but col-orectal cancer can occur at any age.Women and men are affected equal-ly. Though mortality rates have beendeclining slowly over the past 20years, colorectal cancer is the sec-ond leading cause of cancer death inAmerica. Up to 90 percent of col-orectal cancer deaths could beavoided, but sadly, people avoid the

available screening tests. Screeningdetects early cancers and the intes-tinal growths called polyps that canbecome cancerous. When detected atan early stage, colorectal cancer ishighly curable.

My friends who’d been screened had war stories to tell, but I decidedthis was too important to put off. So I did it – I went for my coloncancer screening.

Colonoscopy is the standard forscreening. However, advances inimaging may soon make colonoscopyfor initial screening unnecessary.“Virtual” colonoscopy combinesimaging and computer technologiesto produce a three-dimensionalimage of the entire colon. At thispoint in its development, virtual

colonoscopy isstill not accu-rate enough foruse in routinescreening, but it is hoped thatcontinuedadvances in therequired scan-ning and com-puter technolo-gies will soonmake this possible.

Knowing thatmany peoplehesitate toundergo screen-ing, research isunderway tofind quicker,

non-invasive ways of detecting col-orectal cancer at its earliest stages.For example, researchers are devel-oping stool sampling methods ableto detect genetic changes that sig-nal the presence of cancer. The p53tumor suppressor gene and K-rascancer gene are known to be alteredin many colorectal cancers and canbe detected in stool. Other geneshave been discovered that identifypeople with an hereditary or otherhigh risk of colon cancer; theseindividuals need especially closemonitoring for early signs of cancer.

My doctor also explained the riskfactors for colorectal cancer andwhat a person can do to reduce the risk of getting it.

Risk factors for colorectal cancerinclude a strong family history ofcolorectal cancer or polyps (in afirst-degree relative – that is, parentor sibling – younger than age 60 orin two first-degree relatives of anyage); a personal history of colorectalcancer, polyps, or chronic inflamma-tory bowel disease; or a family withan hereditary colorectal cancer syn-drome (e.g., familial adenomatouspolyposis, hereditary non-polyposiscolorectal cancer). If a person hasany of these known risk factors forcolorectal cancer, screening shouldbe considered earlier than age 50.Genetic tests are available to identi-fy family members with an inheritedpredisposition to the disease. Sincenine out of ten cases of colorectalcancers occur in those older than50, aging also is considered a riskfactor for the disease. Smoking and

P e o p l e ’ s S t o r y

Colorectal Cancer


NCI’s Role

frequent consumption of alcohol andred meat are associated with a high-er colorectal cancer risk.

Eating a diet high in fruits and veg-etables and regular moderate exer-cise may reduce risk. Aspirin use andhormone replacement therapy forwomen after menopause each mayreduce colorectal cancer risk. Thoughit is too soon to recommend thatpeople take supplements to preventcolorectal cancer, limited researchsuggests possible risk-reducing bene-fits of folic acid, vitamin E, seleni-um, and calcium supplements, aswell as a diet containing low-fatdairy products. No one should begintaking aspirin or supplements to pre-vent colorectal cancer without con-sulting a doctor first.

There are certain symptoms that maymean colorectal cancer.

Symptoms, especially in people overage 40, include a change in bowelhabits (constipation, diarrhea, blackor pencil-thin stools) that lasts morethan a few days; a feeling that youneed to have a bowel movement thatdoesn’t go away after you do; rectalbleeding or blood in stool; crampingor gnawing stomach pain; decreasedappetite; weakness and fatigue; andjaundice (yellowing of the skin orwhite part of the eye). Symptomsdon’t mean you have cancer, but see-ing a doctor is the only way to besure. Since a person also can haveno symptoms but still have colorec-tal cancer, the importance of regularscreening cannot be overstressed.

I understand that colorectal cancertreatments are improving, but I’mgoing to keep up the screening anddo everything else I can to prevent it.

For people who do get colorectalcancer, treatment and related carethat enhances quality of life areimproving. Thanks to surgicaladvances, fewer patients now need permanent colostomies (a bag outside the body to hold waste after colorectal cancer surgery).Chemotherapy for colorectal cancerhas improved; new agents and newdrug combinations are now available.

For patients whose cancer has spread,chemotherapy can be given directlyinto the artery that feeds the liver –this may stop further spread of thedisease in the liver and increase sur-vival for some patients. Other excit-ing treatments now in early clinicaltrials include gene therapies designedto deliver normal p53 genes into col-orectal tumors and halt their growth,and several approaches to boostingthe patient’s immune system to bet-ter fight colorectal cancer.

This vignette is a composite of experiences.

Colorectal Cancer Screening Tests

■ Fecal Occult Blood Test (FOBT) – The patient applies samples from three sepa-rate stools on consecutive days to a card. The card is sent to a laboratory tocheck for any traces of blood. Many colorectal cancers cause minor bleedingthat would otherwise go unnoticed. Annual or biennial FOBT screening hasbeen proven to decrease the risk of dying from colorectal cancer.

■ Flexible Sigmoidoscopy – A lighted scope is inserted as far as the lower thirdof the colon to check for growths, cancer, and inflammation. Performed in adoctor’s office, the test takes about 10 minutes following bowel cleansing.While it is 90 percent accurate, it does not examine the entire colon.

■ Colonoscopy – A lighted scope is used to visually examine the entire colon.Usually performed on a hospital outpatient basis, colonoscopy takes about 20 minutes after bowel cleansing. Any polyps found can be removed duringthe test. This test is highly accurate.

■ Double Contrast Barium Enema – An x-ray of the colon is taken followingadministration of a enema containing barium sulfate and expansion of thecolon with air; these two measures enhance the quality of the x-ray image.

■ Digital Rectal Examination – A doctor manually checks the lower part of therectum. This test is used to detect rectal and anal cancer.

To raise awareness that screening saves lives, NCI, the Centers for DiseasePrevention and Control, and the Health Care Financing Administration havelaunched a public education campaign called Screen for Life.


T he national cancer research program repre-sents our Nation’s commitment to progressagainst cancer through science. Science can-

not thrive – indeed, it cannot even take place –without the resources that support an enterprise of discovery. The engine that drives progress is the creativity, commitment, and hard work ofresearchers and clinicians whose discoveries andideas are tested to find ways to understand, pre-vent, detect, diagnose, and treat cancer and tocare for the people who have cancer, have sur-vived it, or are at risk.

SUPPORTING OUR RESEARCHIn support of the community of cancer researchers,NCI has built an infrastructure, or framework, ofsupport mechanisms, organizations, and networksthat link scientists, facilities, and information. It isthis infrastructure that NCI’s budget supports.

Extramural ResearchNCI’s Extramural Research Program serves as ourlink to the greater scientific community andincludes the Divisions of Cancer Biology, CancerTreatment and Diagnosis, Cancer Prevention, andCancer Control and Population Sciences. Anessential component of the Extramural ResearchProgram is NCI program staff. Their scientificexpertise in cancer-related fields and nationalfocus in a given research area enables them towork effectively with NCI-funded scientists inacademia and industry to facilitate researchprogress. They synthesize the state of the sciencein important areas, identify priorities for newresearch directions, foster collaborations amongscientists, keep abreast of the research programthrough active communication with investigators,

organize scientific meetings to promote the inter-change of information among investigators, andsecure supplemental funds as deemed meritorious.Program staff are a resource for researchers, edu-cating them on NCI policies and procedures,advising scientists new to the NCI system on thepreparation of research grant applications, andreviewing and identifying gaps in our researchportfolio that may lead to new areas of researchemphasis. Finally, program staff monitor theprogress of extramural grants through contact withindividual investigators and annual researchprogress reports. Results of these NCI-funded proj-ects are communicated to the scientific communi-ty and the public primarily through peer reviewedscientific journals, but also through major scientif-ic meetings, workshops, and symposia, andthrough our other cancer communication outlets,

How We Work

How We Spend Our Budget

■ About 73% of our budget supports basic and clinicalstudies conducted by researchers and clinicians acrossthe Nation through our Extramural Research Program.

■ We spend about 16% of our budget on our IntramuralResearch Program, in which NCI’s own scientists conduct cancer-related research.

■ About 4% of our budget is devoted to training, education, and career development of researchers and clinicians at every stage of their careers.

■ We use about 3% of our budget to communicate the latest information about cancer risk, detection,prevention, treatment, rehabilitation, and control to people with cancer, health professionals, and the general public.

■ About 4% of our budget supports the administrationand management of the Institute.

such as the Cancer Information Service, thePhysician Data Query database, our press office,and our Web site.

Research Project Grants The main pool of funds expended by NCIfor awards to extramural scientists is knownas the Research Project Grant (RPG) pool.These funds foster the creativity of talentedscientists by providing them with the free-dom to pursue the best ideas that will yieldprogress against cancer.

NCI funds two main types of researchproject grants: Single Research ProjectGrants, awarded to institutions on behalfof individual principal investigators, andProgram Project Grants, funded to fostercollaborations among groups of scientistsinvolved in related research projects. InFY 2000, NCI anticipates expending more than$1.4 billion in support of over 4,300 separateresearch grants. More than 1,150 of these awards

will be new or competing renewal projects. Thesingle investigator grant payline rose from the15th percentile in FY 1995 to the 24th percentile

in FY 1999. These grant awards and thededicated researchers behind them consti-tute the largest single categorical invest-ment of resources that NCI, through theextramural research community, makesannually to combat cancer. Collectively,the Single Research Project and ProgramProject Grants span the full range ofbasic, clinical, population-based, andtranslational studies of cancer etiology,biology, prevention, detection, diagnosis,treatment, control, and survivorship. Theadvances that come from these invest-ments, such as the discovery and develop-ment of paclitaxel (Taxol®) and tamox-ifen (Nolvadex®), and advances in the

understanding of basic bone marrow transplantbiology and clinical application, represent thefuture of cancer research and cancer care.

Other Grant Mechanisms NCI also has special mechanisms for exceptionallyhigh-risk, innovative, exploratory, and develop-mental research activities, to allow investigators toembark on projects of unusual scientific potential,and to support research and development ideasthat are likely to result in the development of acommercial product or service.

Support for Extramural Clinical Research Clinical research is one of the cornerstones of theNational Cancer Program. Every new treatmentwe use today, every preventive measure that iswidely recommended, and every innovative detec-tion strategy was, at one time, tested in cancer

How

We W

ork

How We Work 25

A complete

listing and

description of

NCI’s grant

mechanisms can

be found at

http://deainfo.

nci.nih.gov/

flash/awards.

htm

Research Project Grants (RPGs)(dollars in thousands)

1999 2000 2001Operating President’s CoreBudget Budget Budget

Ongoing $983,129 $1,056,342 $1,166,993New 377,516 353,517 366,244Subtotal 1,360,645 1,409,859 1,533,237Small Business 57,808 60,978 63,173Innovation Research

TOTAL $1,418,453 $1,470,837 $1,596,410

http://deainfo.nci.nih.gov/flash/awards.htm

patients or in people at risk for the disease. Theseheroes of the fight against cancer have allowed usto amass the body of information we are buildingupon every day. Even though trials often test thelatest therapies, there is no guarantee of success –a person may be randomly assigned to a controlgroup to receive standard therapy, or may partici-pate in a Phase I or II trial which may be too earlyin the drug’s development to know if it is effec-tive. Nonetheless, trials provide patients and otherparticipants access to cutting-edge interventionsand provide researchers with information that ulti-mately will enable us to prevent and effectivelytreat all cancers.

A strong clinical research infrastructure, includ-ing a comprehensive program of clinical trials intreatment, early detection, and prevention, is avital component of NCI’s research program. NCI’sCancer Centers, Cooperative Groups, andCommunity Clinical Oncology Program are wherefindings from the laboratory are translated intonew treatments, diagnostic tools, and preventiveinterventions, and where these measures are firsttested for safety and effectiveness. These programsare fundamentally interrelated: every CancerCenter is a participant in at least one CooperativeGroup, and Cooperative Groups serve as researchbases for participants in the Community Clinical

Oncology Program. Hundreds of clinical trials aresupported through these and other research mech-anisms, such as Single Research Project Grants,Program Project Grants, cooperative agreements,and contracts.

NCI’s programs in clinical research haveenjoyed many notable successes over the years.NCI has been responsible for the early develop-ment and/or testing of many important treat-ments, including paclitaxel (Taxol®) for breastand ovarian cancer, interferon alpha-2b for malig-nant melanoma, and Herceptin® for breast can-cer. Studies to test the effectiveness of certaindrugs to prevent first occurrences of cancerinclude the ongoing Prostate Cancer PreventionTrial. The Breast Cancer Prevention Trial demon-strated a 49 percent reduction in breast cancerincidence during the treatment period amonghigh-risk participants who took the drug tamox-ifen (Nolvadex®). Based on the results from thattrial, the Food and Drug Administration hasapproved the use of tamoxifen to reduce thechance that women at high risk of breast cancerwill develop the disease.

Through our clinical research programs, we alsohave identified successful interventions for symp-tom management and continuing care of cancerpatients, including treatment for mouth sores andhot flashes, both common side effects ofchemotherapy. And based on the results of labora-tory research, we now are exploring interventionsfor individuals whose genetic profile places themat increased risk of cancer.

However, our ability to conduct clinical trials isin danger of being compromised by changes in thehealth care system. In the past, institutions haveused surplus revenues from patient care services tosupplement government research support. Thegrowth of managed care has all but eliminatedthose discretionary funds. As a result, institutionscan no longer sponsor research activities requiringcapital expenditures and cannot support essentialtraining for young investigators. These changespose a very real danger for the continuation ofcancer research and our continued progress againstcancer.

In response to the changing health care system,we are developing ways to improve access to andparticipation in clinical trials. To ensure thatphysicians have the time to conduct clinical trials,


Clinical Trials Infrastructure(dollars in thousands)

1999 2000 2001 Operating President’s CoreBudget Budget Budget

TREATMENT:Clinical $126,205 $125,460 $129,977Cooperative ResearchCommunity 6,565 6,007 6,009Clinical OncologyProgram

Subtotal 132,770 131,467 135,985Treatment

PREVENTION:Community 45,596 48,305 50,258Clinical OncologyProgram

TOTAL $178,366 $179,772 $186,244

How We Work 27

How

We W

ork

What are Clinical Trials?

Clinical trials are research studies conducted to answerspecific scientific questions about new ways to pre-

vent, diagnose, detect, and treat cancer. Most clinical tri-als are designed to test new cancer treatments; concurrentor separate studies also may look at the psychologicalimpact of cancer or ways to improve a patient’s quality oflife. In addition, the number of clinical trials to test drugsfor cancer prevention has been increasing, because of suc-cess with large precedent-setting prevention trials, such asthe Breast Cancer Prevention Trial.

Before a clinical trial of a promising new treatment orpreventive agent can be launched, the agent must undergorigorous laboratory testing to prove that it may be benefi-cial to patients and will be safe to use during testing. If the agent is promising and is safe for use, thenresearchers design a trial in an effort to answer a specificscientific question about the agent’s use or efficacy. Theresearchers then establish strict entry criteria to helpidentify patients who are best suited for the trial. Onlythen can the researchers recruit volunteers to participate.Trials generally are conducted in three phases:

■ Phase I — These are small trials designed to tellresearchers how best to administer the new interven-tion and, in studies of new agents, the optimal dose ofthe drug to give with the least possible side effects.

■ Phase II — Involving a small number of people,these studies determine if the treatment, delivered atthe optimum dose, destroys or prevents cancer andagainst what types of cancer it works best.

■ Phase III — Once a new therapy has been proven tohave an anti-cancer effect and be safe, it then movesto a Phase III trial to compare its efficacy with that ofa standard therapy. Phase III trials often are large, andmay include hundreds or thousands of people fromacross the country.

As each phase of testing is completed, the data col-lected are analyzed and the results published. Based onthis analysis, the researchers determine whether the agentis showing enough of a benefit to continue testing. Oncea therapy has successfully completed these three phases oftesting, a New Drug Application is submitted to the U.S.Food and Drug Administration. The testing and approvalprocess can take many years; however, the approvalprocess can sometimes be accelerated, particularly if theagent is beneficial for patients with a form of cancer thathas few treatment or prevention options. Occasionally,additional trials (called Phase IV trials) are conductedafter the approval of the drug to provide longer-term safety data or to collect new types of information, such asquality of life assessments.

Ensuring Diversity in Clinical TrialsParticipation

Ensuring participation in clinical research, particularlyamong women and members of special population

groups, is a high priority for the Institute; several pro-grams help us ensure that all populations are well repre-sented. The Minority-Based Community Clinical OncologyProgram, begun in 1990, has been successful in accruingminority cancer patients to trials and provides for studiesin minority populations that may lead to better under-standings about the dynamics of patient accrual. In addi-tion, two new grant programs are supporting research onways to draw more women and minority participants intoprevention and screening studies. The Institute also hasfunded a number of conferences aimed at sharing currentinformation and strategies to maintain and enhance itsgood record of minority accrual to clinical trials.

As a result of our efforts, analysis of accrual patternsin Cooperative Group cancer treatment trials has shownthat women and ethnic/racial minorities are proportionallyrepresented in NCI cancer treatment trials. Nearly 20 per-cent of the more than 20,000 patients entering treatmentclinical trials every year are members of an ethnic/racialminority group.

Understanding Clinical Trials


we have developed a Midcareer InvestigatorAward in Patient-Oriented Research that offerssubsidies to clinicians, allowing them protectedtime to devote to vital patient-oriented research.Further, through agreements with private insurersand other government agencies, we are working toassure insurance coverage for individuals partici-pating in trials. We have two government intera-gency agreements, one with the Department ofDefense (DoD) that provides coverage for DoDhealth plan beneficiaries to participate in NCI-sponsored cancer treatment trials, and asecond with the Veteran’s Administrationthat covers the full range of NCI-spon-sored clinical trials. This year, we signed anew agreement with the DoD, markingthe first time a health plan has agreed toprovide coverage for participation in can-cer prevention trials. Based on these ini-tial successes, several organizations haveenacted agreements at the local, state,and national levels to provide greateraccess and coverage for clinical trials. Forexample, in 1999 the United Health CareCorporation began piloting a programproviding coverage of the patient carecosts associated with cancer treatment tri-als conducted by the NCI-supportedCoalition of Cooperative Groups. Severalstates also have enacted legislationdesigned to provide greater access and coverage forclinical trials. In addition, NCI is working withpatient advocates, local communities, and non-profit organizations to increase awareness of andeducation about clinical trials. Together withother clinical trials efforts, we hope these initia-tives will serve as national models and provideaccess for more individuals interested in partici-pating in clinical trials.

Cooperative Group Clinical Trials ProgramThe sheer number of different types of cancer andtheir biological complexity make the process ofefficiently identifying and evaluating new treat-ments or other anti-cancer strategies extremelychallenging. To test potential treatment advancesin patients more rapidly, NCI maintains theCooperative Group program, a national network

of 12 consortia (Cooperative Groups) that seek todefine the key unanswered questions in cancer andthen conduct clinical trials to answer them. Eachyear, 1,700 institutions throughout the UnitedStates and Canada, and approximately 8,000investigators in these institutions participate inthese trials. This kind of cooperation makes it pos-sible to centralize administration and data collec-tion for trials taking place at a large number ofsites around the world. The Cooperative Groupsdiffer in structure and research organization, but

they share the common purpose of devel-oping and conducting large-scale trials inmulti-institutional settings.

Cooperative Groups frequently worktogether when the cancer in question is sorare that one group working alone wouldbe unable to accrue enough patients toconduct a meaningful study. For example,six Cooperative Groups worked togetheron the landmark study establishing thatall-trans retinoic acid (ATRA) significant-ly improves disease-free survival time forpatients with acute promyelocyticleukemia. Cooperative Groups collaborateregularly on clinical trials for solid tumorsin children, breast cancer, colorectal cancer, lung cancer, prostate cancer, andcancers of the head and neck.

Approximately 20,000 patients partici-pate in Cooperative Group clinical trials each year,principally in large Phase III trials that help estab-lish the state of the art for cancer therapy. Manynew anti-cancer drugs are tested in patients for thefirst time under NCI Investigational New Drug(IND) sponsorships through the CooperativeGroup program. Nearly 200 investigational agentsor treatment strategies, ranging from newchemotherapy drugs and cancer vaccines to agentsthat prevent tumor blood vessel development, arecurrently being studied under NCI INDs.

An agreement between the U.S. Office forProtection from Research Risks and the EuropeanOrganization for Research and Treatment ofCancer (EORTC) promises to improve the abilityof NCI’s Cooperative Groups to collaborate with the EORTC and other international cancerresearch groups.

To learn more

about the

Cooperative

Group program,

visit the

Cooperative

Group Web

site at

http://ctep.

info.nih.gov/

CoopGroup/

Coop_Group_

Prog.html

http://ctep.info.nih.gov/CoopGroup/Coop_Group_Prog.html

How We Work 29

How

We W

ork

Community Clinical OncologyProgram (CCOP)The Community Clinical OncologyProgram is a network of 49 central officesin 31 states that provides the infrastruc-ture to link more than 2,500 communitycancer specialists and primary care physi-cians with clinical Cooperative Groupsand Cancer Centers. In addition, CCOPssupport scientific development and theimplementation of ongoing cancer treat-ment, prevention, and control clinical tri-als among community Cooperative Groupmembers and Cancer Centers.

This network enables individuals toparticipate in state-of-the-art clinicalresearch trials at over 340 communityhospitals without the burden of travelingto a distant site. Each year, the Programenrolls more than 5,000 patients in cancertreatment clinical trials and an additional3,500 patients in cancer prevention and controlclinical trials. An additional seven Minority-basedCCOPs increase the participation ofminority individuals in clinical trialsresearch. Each year, over 700 patientsenter clinical trials through these special-ized CCOPs. Located in six states andPuerto Rico, these programs bring anadditional 33 hospitals and 250 physiciansinto the clinical trials network. Byincreasing the number of patients andphysicians who participate in clinical tri-als, the program helps transfer the latestresearch findings to the community.

Cancer Centers Fifty-nine research-oriented institutions through-out the Nation have been designated NCI-sup-ported Cancer Centers in recognition of their sci-entific excellence. The Centers are key partners inNCI’s efforts to speed the process of discovery andbring the benefits of cancer research directly tothe public. Located throughout the country, eachCancer Center is a hub of cutting-edge research,high quality cancer care, and outreach and educa-tion for both health care professionals and thegeneral public.

When an institution meets the rigorous com-petitive standards to become an NCI Cancer

Center, it is awarded a Cancer CenterSupport Grant. These funds enable theinstitution to coordinate multidisciplinaryapproaches to research questions, to gainaccess to the most advanced researchtechnologies, and to take rapid advantageof new research opportunities. Support forthe Cancer Centers helps ensure a closeassociation between state-of-the-artresearch and state-of-the-art care activi-ties within the institution. Moreover, itallows each Center to develop key collab-orations with industrial, community, andstate health organizations, and to link theresearch capabilities and expertise of sci-entists within the institution to problemsof cancer incidence and mortality in theircommunities and regions.

Three types of centers exist: CancerCenters have specific research foci, suchas epidemiologic or basic research;

Clinical Cancer Centers integrate basic sciencewith clinical science; and Comprehensive Cancer

Centers demonstrate both significant sci-entific strength in basic, clinical, andpopulation studies and strong interdisci-plinary collaboration. ComprehensiveCancer Centers also must have in placeeffective cancer information, education,and outreach activities for the regions andcommunities they serve.

Traditionally, Cancer Centers have hadbroad scientific bases, and most have beendeveloped within a single institution.Changes in the program, however, are

Cancer Centers (dollars in thousands)


Basic $13,504 $18,765 $19,441Clinical/ 134,738 137,014 141,947ComprehensiveSubtotal 148,242 155,779 161,387Core GrantsPlanning 1,131 787 815SPOREs (P50) 48,117 40,889 42,361

TOTAL $197,490 $197,455 $204,563

More information

on the

Community

Clinical Oncology

Program is

available at

http://dcp.nci.

nih.gov/corb/

CCOP.html

The Minority-

based CCOP Web

site is located at

http://dcp.nci.

nih.gov/corb/

MBCCOP.html

The Cancer

Centers program

Web site is

located at

http://www.nci.

nih.gov/

cancercenters/

http://dcp.nci.nih.gov/corb/CCOP.html

http://www.nci.nih.gov/cancercenters/

http://dcp.nci.nih.gov/corb/MBCCOP.html

enabling the planning of new consortia of institu-tions, often linking free-standing clinical and aca-demic centers with community hospitals to formnetworks with tremendous research strength andthe ability to deliver quality care in a managedcare environment. In addition, more focused sci-entific concepts are being developed for CancerCenters. For example, some Centers are focusingon population sciences and others are concentrat-ing on translational research opportunities withina specific scientific discipline, such as immunolo-gy. Overall, such changes in the Cancer Centersprogram promise to increase the scientific versatil-ity, translational research capabilities, and geo-graphic distribution of NCI-supported CancerCenters.

Intramural Research The NCI Intramural Research Program (IRP),consisting of more than 400 principal investigatorsin the Divisions of Basic Sciences, CancerEpidemiology and Genetics, and ClinicalSciences, is dedicated to the comprehensiveunderstanding of cancer and to finding cures forthese diseases. Organized to complement ongoingresearch in universities and in industry, the IRP

has been involved in pivotal discoveries in cancerresearch: the first successful treatments for child-hood leukemias; establishing the principles forcurative chemotherapy for lymphomas; developingeffective therapies for HIV; defining the founda-tions for tumor vaccines; identifying the geneticcauses for familial cancers; and uncovering envi-ronmental causes of cancer.

The IRP’s epidemiology research program is anational program of population-based studies toidentify environmental and genetic determinants of


Intramural Research (dollars in thousands)


Basic $173,218 $172,602 $179,506Clinical 117,039 116,623 121,288Epidemiology 48,987 48,823 51,156& GeneticsNIH Central 149,640 149,097 154,681Services

TOTAL $488,884 $487,144 $506,630

S P O T L I G H T O N R E S E A R C H

NCI’s Intramural Program

NCI’s Intramural Research Program (IRP) is a criti-cal part of the effort to understand and find cures

for the many types of cancer. New programs include:

Our recently established Advanced Technology Center(ATC), home to the Cancer Genome Anatomy Project(CGAP), two high throughput genotyping and sequenc-ing centers, and a microarray facility, that uses newtechnologies to address biological, clinical, and geneticquestions pertinent to human cancers. The ATC, whichfocuses on clinical and molecular medicine, housesinvestigators from NCI and from the National HumanGenome Research Institute, whose research centers onhuman cancer genetics, molecular epidemiology, andcell biology. Through the efforts of CGAP and array proj-ects, ATC has become a premier facility for the develop-ment of tools for molecular expression profiling studies.

NCI is initiating a joint effort with the National Instituteof Neurological Disorders and Stroke to develop a Neuro-Oncology Branch at the NIH Clinical Center. Researcherswill study both adult and childhood brain tumors from atranslational perspective, applying advances in theunderstanding of the basic biology of central nervoussystem malignancies to novel, targeted treatments.

In support of NCI’s long tradition of using mice as models for human cancers, a new Mouse GenomicsProgram will bring together scientists with varied butrelated expertise in the field to create an environmentfor rapid progress in this area. The program will developnew disease models based on advances in the develop-ment of high-resolution genetic and physical linkagemaps of the mouse genome, transgenic technology, andarray technologies. These models will offer a potentiallyimportant resource for preclinical testing of differenttreatment strategies.

cancer. This IRP component supports epidemiolog-ic and interdisciplinary research to ensure that themomentum of recent and ongoing discoveries inmolecular genetics and cancer biology is acceleratedand broadened through population-based studiesinto the etiology of cancer and its prevention.

The intramural clinical research program isconducted principally in NIH’s Warren G.Magnuson Clinical Center. It provides the oppor-tunity for patients from across the country to betreated through ground-breaking research proto-cols. The Clinical Center is a unique environmentin which investigators throughout the NIH com-munity develop and test novel therapies derivedfrom our growing body of knowledge; in this envi-ronment new information can be transferredquickly from the laboratory to the patient andback to the laboratory for additionalanalysis.

The Intramural Research Program isuniquely structured to address cancerresearch problems whose resolutionrequires long-term commitments and thatmay be considered unsuitable for manyextramural funding mechanisms. Anotherunique aspect of the Intramural Programis its framework for cooperation betweenbasic researchers and investigators per-forming clinical trials. These interactions, fosteredby common research interests, topic-specific focusgroups and retreats, and close physical proximityof basic and clinical research efforts, result in rapidtranslation of new basic research discoveries intoearly clinical trials.

Because of its national stature and unique struc-ture, NCI’s IRP also is a center for basic, clinical,and population-based oncology training forresearchers, clinicians, research fellows, and visit-ing scholars from around the world. NCI plays amajor role in fostering the education and careersof a growing number of nurses, doctors, and physi-cian assistants, as evidenced by the approximately500 participants each year in the summer intramu-ral research training program. Many of the currentleaders in cancer research received some of theirtraining at NCI, and we anticipate that the IRPwill continue to be an important resource fortraining the next generation of investigators.

Cancer Control Cancer control research encompasses basic andapplied research in the behavioral, social, andpopulation sciences aimed at creating or enhanc-ing interventions that, by themselves or in combi-nation with biomedical approaches, reduce cancerrisk, incidence, morbidity, and mortality, andimprove quality of life. For example, a cancer con-trol study might investigate the use of a medicalintervention, such as a nicotine patch, in combi-nation with a behavioral intervention, such as acounseling program to help smokers overcometheir barriers to quitting. Interventions may bedirected at patients, physicians, and/or otherhealth care providers. Cancer control researchseeks to improve interventions across the humanlifespan and over the entire cancer continuum,

and to move research findings into clini-cal and public health practice. The foun-dation of cancer control research is epi-demiology, and surveillance and outcomesresearch are the fundamental mechanismsfor assessing progress.

NCI maintains a firm commitment tocancer control research through theDivision of Cancer Control andPopulation Sciences (DCCPS), the focusfor NCI-sponsored research programs

aimed at studies in populations, behavior, surveil-lance, special populations, outcomes, and otheraspects of cancer control. Our wide-ranging cancercontrol research efforts include research in epi-demiology and genetics, tobacco research, tailoredcommunications, and theoretical models for stud-ies of human behavior and behavior change.

How

We W

ork

How We Work 31

For more

information on

the NIH Clinical

Center visit

http://www.cc.

nih.gov

Cancer Control (dollars in thousands)


Grants $107,549 $113,671 $127,734Contracts 103,828 116,408 120,599Cancer Control 89,882 82,640 85,946Management & Support

TOTAL $301,259 $312,719 $334,278

http://www.cc.nih.gov/

Cancer surveillance – tracking and analyzingtrends in cancer incidence, mortality, and survivalrates – is a critical component of cancer control.The keystone of NCI’s surveillance efforts is theSurveillance, Epidemiology, and End Results(SEER) program, which monitors the Nation’scancer burden and provides the basis for assessingindividual, organizational, and societal factors thatcan reduce cancer rates. (See page 92 for furtherinformation on cancer trends.)

AIDS ResearchMalignancies occur in more than 30 percent ofAIDS cases and contribute greatly to AIDS mor-bidity and mortality. Many areas of fundamentalbiology developed in NCI programs, includingvirology, immunology, and cellular and molecularbiology, are directly applicable to understandingHIV and AIDS. Research efforts in AIDS malig-nancies begins with basic science that providesnew insights in cancer biology that can lead tohypotheses to test in epidemiologic studies, thedevelopment of treatment targets, and new treat-ments to prevent and control AIDS malignancies.But basic science, even with associated drug devel-opment programs, would not make progress with-out clinical programs in which to test potentialdiscoveries. Work in this area is necessarily collab-orative and one of NCI’s major roles is to fosterthese collaborations, create research groups, andprovide infrastructure, including clinical trials sup-port, central specimen banking, international sci-entific meetings, and new investigator training.

Today, research into the fundamental biology ofHIV and AIDS, AIDS treatment, and particularlyAIDS-related malignancies takes place throughoutall programmatic mechanisms of NCI. TheIntramural Research Program is an internationallyrecognized center for research in HIV and AIDS,housing the HIV Drug Resistance Program, theHIV and Malignancies Branch, and the NIHVaccine Research Center, a joint project with theNational Institute of Allergy and InfectiousDiseases. The Extramural Research Program alsohas been a vital and innovative force in this areaof research. Among its programs are the AIDSMalignancy Consortium, the AIDS MalignancyBank, the AIDS Oncology Clinical ScientistTraining Program, and an annual international

forum on AIDS malignancies.NCI, in coordination with other NIH Institutes

and the NIH Office of AIDS Research, continuesits commitment to meeting the challenge of AIDSand is working to ensure that NCI-supportedAIDS and AIDS-related research is integratedwith national AIDS strategies.

Training and Education In the past decade, we have made stunningadvances in our understanding of cancer. Our abil-ity to bring these new discoveries to the communi-ties and clinics where they benefit cancer patientsand those at risk for developing cancer depends onphysicians and other scientists who are speciallytrained in cancer research. While resources fortraining are shrinking at many institutions, NCI iscommitted to ensuring that a national cadre oftrained cancer researchers exists by continuing toprovide essential training to our Nation’s scientificand medical workforce.

To address this crucial requirement, NCI hasdeveloped a strategic plan for extramural training,education, and career development. This planfocuses on attracting young scientists into cancerresearch, on providing stability and protectedresearch time for researchers in disciplines criticalto translational research, on creating more oppor-tunities for underserved ethnic and minority scien-tists, and on encouraging research program diversi-fication. In pursuit of these objectives, NCI has


Training and Education(dollars in thousands)


National Research 57,135 58,026 60,115Service AwardsResearch Career 34,881 38,915 40,316ProgramCancer Education 17,319 16,692 17,293ProgramMinority 2,788 3,623 4,373Biomedical Research Support

TOTAL $112,123 $117,256 $122,097

implemented a number of new training and careerdevelopment programs in basic, clinical, popula-tion, and diversified sciences, as well as for under-served ethnic and minority groups who are under-represented in the research workforce. These pro-grams aid investigators in stabilizing and sustain-ing productive research careers, and offer opportu-nities for engaging in translational research (seepage 96 for more information on training).

NCI’s research divisions also are developingtraining programs. For example, the Division ofClinical Sciences’ Clinical Intramural ResearchAward supports innovative and collaborative clini-cal research projects emphasizing novel approach-es or promising new outcomes of current research;the Division of Cancer Epidemiology andGenetics’ Cancer Genetics and EpidemiologyFellowship Program provides interdisciplinarytraining in clinical, molecular, and quantitativegenetics, and genetic epidemiology; and theDivision of Cancer Prevention Fellowship pro-vides training in cancer prevention and control forindividuals from many health science disciplines.

Other Research Support In addition to its many types of grants and awards,NCI employs a variety of other research supportmechanisms. These mechanisms include: contractsto provide support for research, information

Informing Professionals and the Public — NCI’s Information Services

Every day, thousands of people – health professionals,cancer patients and their families, and the general

public – benefit from NCI’s broad array of informationand public education services. Using basic printed materials, sophisticated Internet technology, andeverything in between, NCI provides millions of peopleeach year — often in Spanish as well as English —with the complete, reliable information they need tomake decisions about cancer prevention, detection,treatment, and follow-up care. NCI’s services include: ■ The Cancer Information Service (CIS). This nation-

wide cancer information and education network,available in all 50 states, Puerto Rico, and the U.S.Virgin Islands, receives more than 2,000 calls eachday. By calling 1-800-4-CANCER (1-800-422-6237),cancer patients, their families, people at risk for cancer, and health professionals can receive informa-tion confidentially on all aspects, including preven-tion, treatment and clinical trials. Callers with TTY equipment can dial 1-800-332-8615.

■ NCI’s Internet Services. Patients and health profes-sionals with access to the Internet may search foraccurate, up-to-date information about cancer on:NCI’s Web site (http://www.nci.nih.gov) or theInternational Cancer Information Center’s CancerNetTM

Web site (http://cancernet.nci.nih.gov) andcancerTrials™ (http://cancertrials.nci.nih.gov).

■ Physician Data Query (PDQ®). The CancerNetTM

searchable PDQ® data base contains current infor-mation on cancer prevention, screening, treatment,and supportive care, as well as descriptions ofactive clinical trials and directories of physicians,health professionals who provide cancer geneticsservices, and organizations involved in cancer care.

■ CANCERLIT®. This bibliographic data base containsmore than 1.4 million records on cancer literaturefrom 1963 to the present. It can be searched fromthe CancerNetTM Web site.

■ The PDQ/CANCERLIT® Service Center. Physiciansand other health professionals can make requestsfor PDQ and CancerLit information through a toll-free telephone service (1-800-345-3300), e-mail([email protected] with the word“help” in the body of the message, users receive acontents list and ordering instructions by returnelectronic mail.), or fax (301-402-5874).

■ Print Publications. NCI makes available nearly 600 publications and audiovisual materials, manypublished both in English and Spanish. They areavailable from the toll-free number 1-800-4-CANCERor from the NCI Web site. NCI is also working todevelop materials in several Asian languages.

How

We W

ork

How We Work 33

Other Research Support(dollars in thousands)


Research $275,087 $298,569 $309,519Support ContractsScientific 3,528 3,742 3,877Evaluation GrantsResearch 19,437 21,338 22,106Resource GrantsConstruction 3,000 3,000 5,000Conference Grants 901 1,101 1,141Research 108,965 110,065 114,468Management & Support

TOTAL $410,918 $437,815 $456,111



Addressing the Unequal Burden of Cancer —Special Populations Research

Not all populations are affected equally by cancer.Cancer statistics and numerous studies have shown

that some population groups develop cancer more often,have poorer survival, and are more likely to die fromcancer than others. These “special” populations, whichare not mutually exclusive, include ethnic minorities,geographically isolated and other medically underservedpopulations, the elderly, women, people of diverse cul-tures and lifestyles, and people with lower income, edu-cation, and literacy levels. We know that major differ-ences in cancer burden exist between these groups andthe general population. Moreover, disparities exist with-in and between special populations, who likewise areaffected more severely by many specific types of cancer.

Research also is demonstrating that differences in can-cer morbidity and mortality previously attributed to raceare not due to supposed biological differences betweenpopulations or between the tumors individuals develop.Rather, these differences actually reflect the too-fre-quent biological and medical consequences of socially-defined race – lower socioeconomic status and educa-tional level, and less access to high quality cancer care.For example, recent data from NCI’s Black-White Studyof Cancer Survival showed that compared with whitewomen, black women with breast cancer (as well aspoor and older women) were less likely to receiveappropriate treatment after diagnosis. They also aremore often diagnosed at a later stage of disease and areless likely to have a regular source of health care.Similar disparities in appropriate treatment have beendemonstrated between various population groups withprostate, lung, colorectal, and cervical cancers. Analysesof NCI clinical trials have shown however, that equaltreatment yields equal outcome, and that race is not afactor when there is equal treatment.

NCI has long supported and is committed to a broad arrayof research and related activities to pinpoint, understand,and address cancer disparities. NCI plans and coordinatesthese activities through organizational units dedicated tospecial populations issues. The Office of SpecialPopulations Research was established in 1996 to advisethe Director of NCI and provide a focal point for leader-ship and coordination on minority and other special popu-lations research. NCI’s Comprehensive MinorityBiomedical Branch creates and coordinates programs tobroaden participation in all aspects of cancer-relatedresearch and training activities by minorities and otherspecial populations. The Applied Sociocultural ResearchBranch (ASRB) promotes grant-supported cancer preven-tion and control research in populations that experience agreater burden of cancer. The ASRB also offers training tohelp potential applicants prepare scientifically competitiveresearch applications in cancer control science. Specialpopulations initiatives at NCI now are expanding even fur-ther to encompass a larger spectrum of special popula-tions, and to create new opportunities to attract and traincancer researchers and clinicians from special populations.

For more than 20 years, NCI’s Surveillance, Epidemiology,and End Results (SEER) cancer registry program has mon-itored the Nation’s cancer burden and been a world modelfor tracking population trends in cancer incidence, sur-vival, morbidity, and mortality. SEER data are used byresearchers to develop studies designed to explain cancertrends and identify study populations, by health plannersand policy makers at all levels, by public health practition-ers, and by the public. SEER now is being expanded to col-lect data on a wider range of population subgroups and onsocioeconomic and other factors that underlie cancertrends. As many as four new state registries will be addedto SEER, and up to ten additional states will receive sup-

dissemination, and management; conferencegrants to fund meetings, conferences, and work-shops; resource-related research projects toimprove the ability of resources to serve biomed-ical research; scientific evaluation awards to sup-port the scientific review of grant and contractproposals; and construction grants and contracts

to provide partial support for the modernization ordevelopment of cancer research facilities through-out the Nation.

NCI also sustains, guides, and monitors boththe extramural and intramural activities of theInstitute through its research management andsupport activities. These activities include overall

How We Work 35

How

We W

ork

plementary funding to upgrade their existing registries tomeet SEER standards. This expansion will be achieved inpartnership with the Centers for Disease Control andPrevention, and will capture data on a broader spectrum of Native American and Hispanic population subgroups,rural African Americans and whites, and others.

NCI recently launched the Special Populations Networksfor Cancer Awareness Research and Training, for which$30 million has been earmarked over five years. Funding adiverse group of research projects aimed at improvingcancer prevention and control in minority and underservedcommunities, the Networks will build upon and expandthe scope of NCI’s three National Leadership Initiativesthat now are drawing to a close. The LeadershipInitiatives were instrumental in launching collaborativeefforts to raise cancer awareness, improve access to care,and reduce the cancer burden in African American,Hispanic, and Appalachian populations. Principal goals ofthe new Networks will be to develop and maintain part-nerships between scientific researchers and communityleaders in a broader range of minority and underservedpopulations, develop and test community cancer aware-ness activities, support minority enrollment in clinical tri-als, and encourage minority scientists to participate inresearch. Initial awards under the program will be made inMarch 2000.

Also responding to the need to attract, develop, and sup-port researchers and cancer care givers from minority andunderserved populations, NCI recently organized andexpanded special populations biomedical training opportu-nities under the Continuing Umbrella of ResearchExperiences (CURE) initiative. CURE reaches minoritystudents as young as high school age, develops under-

graduate, graduate, and postdoctoral scientists, and sup-ports young minority investigators as they establish theirresearch careers. CURE also provides training support forindividuals with disabilities and for scientists re-enteringan active research career after taking time off for childcare or other family responsibilities. In addition, long-term partnerships between NCI Cancer Centers andboth minority and minority-serving institutions arebeing established. The partnerships are expected toenhance the cancer centers’ approaches to outreach andeducation for underserved communities as well as theinstitutions’ approaches to conducting cancer research andtraining future cancer scientists.

In July 1999, NCI convened a meeting of key staff andidentified experts to discuss how best to describe under-served populations to aid NCI in planning, research, andrelated activities to address cancer issues in these popula-tions. In addition, NCI has appointed a SpecialPopulations Working Group to enhance its priority-setting and information dissemination processes andstrengthen communication with the many groups, organi-zations, and institutions involved in special populationsissues. Its membership is drawn from a variety of medicaland non-medical disciplines, individuals knowledgeableabout the cancer experience, and diverse communities.The Working Group is charged to raise and articulate spe-cial populations concerns and issues, make recommenda-tions for addressing special populations issues at the NCI,suggest NCI-community partnerships to reach commongoals, and provide an ongoing communication channelwith diverse minority and special populations communi-ties. This important group met for the first time in May1999 and will meet approximately three times per year.

scientific program direction and administration bythe Office of the Director, with assistance fromgrant and contract science managers, finance,human resources, legislation, science programdirection and assessment, and technology transferstaff. The review and oversight activities of theNational Cancer Advisory Board and President’s

Cancer Panel also are included. This part of thebudget also supports a share of central NIH facili-ties and operations, and extramural program staffsalaries (intramural staff salaries and intramuralfacilities maintenance are included under theintramural research budget).


Extraordinary Opportunities for Investment

O ver the past thirty years, we have witnesseddramatic changes in our fight against cancer.The revolution in molecular biology, along

with the emergence of powerful new technologies,have enabled us to gather an impressive body ofknowledge about cancer’s very nature. Today we areable to identify many of the biochemical pathwaysin a cell that become disrupted in cancer, and weare gaining a fuller understanding about how suchchanges contribute to a cancer cell’s abnormal anddangerous behavior in the body. We also are gain-ing important insights into how the vulnerability ofDNA – our genetic material – and elements in ourenvironment and lifestyle interact to give rise tothis disease. For the many who struggle with cancer,these striking changes in the science and technolo-gy of cancer research are reflected in markedimprovements in treatments and a heightenedchance for survival. They also are reflected in moreeffective prevention, particularly for those who maybe at increased risk for the disease. These areimportant advances, yet as long as people continueto suffer from cancer, our work is not complete.

Three years ago, NCI acknowledged that to con-quer cancer, we must choose a path that not onlymaintains our pace of discovery but one that speedsprogress and optimizes our ability to overcome thisdisease. This path is great science – science that isanchored in exceptional quality, marked by vision,imbued with imagination – a path that tenaciouslyfollows opportunities for discovery. In 1996, NCIidentified areas of extraordinary opportunity forinvestment in cancer research. We defined areas ofdiscovery in which focused efforts and increasedresources could produce dramatic progress towardreducing the burden of cancer. If pursued, theseextraordinary opportunities for investment – newdoors to discovery opened by past successes – wouldprovide profound insights into how cancer devel-

ops, paving the way for better techniques to pre-vent, detect, diagnose, and treat the disease.

Four areas originally were chosen as investmentareas – Cancer Genetics, Preclinical Models ofCancer, Imaging Technologies, and Defining theSignatures of Cancer Cells. Since selecting theseareas in 1996, we have focused on putting into placeseveral dozen innovative projects – the CancerGenetics Network, the Mouse Models of HumanCancers Consortium, In Vivo Cellular and MolecularImaging Centers, and the Cancer Genome AnatomyProject (CGAP), to name a few – that provide theinfrastructure for basic discovery. Many of these proj-ects are described in the following pages.

This year, we intensively evaluated our currentdirection and progress in each investment area tochart a course for our second generation of efforts.We determined that our primary focus for each ofthese extraordinary opportunities should be tomove from process to product in the coming years –to use the infrastructure established in each area toresolve fundamental questions about cancer andproduce tangible improvements in cancer detec-tion, diagnosis, and treatment. For example, ourcharge now will be to take cancer genes identifiedthrough CGAP and determine how they contributeto cancer, how they can easily be detected in peopleat risk, and how they can be targeted through newtreatments. From this evaluation, we also deter-mined that we should broaden our Cancer Geneticsinvestment area to Genes and the Environment,and integrate our efforts in Preclinical Models intothe other investment opportunities.

We also identified three new areas of extraordi-nary opportunity for investment: Research onTobacco and Tobacco-Related Cancers, CancerCommunications, and Molecular Targets ofPrevention and Treatment. As with the opportu-nities identified originally, each of these areas is

rife with possibilities for taking us to a new era incancer prevention and cancer care.

An investment in each of these six areas prom-ises to drive forward our understanding and con-trol of cancer. Although the needed resources arenot trivial, our failure to respond quickly withinvestment in all of these areas will slow the paceof cancer research at all levels – and more impor-tantly – will impair our ability to better care forthose whose lives have been touched by cancer.

Extraordinary Opportunities 37

Opportunities

CancerCommunications

11% Genes and theEnvironment

17%

CancerImaging

15%

Defining theSignatures of Cancer Cells

23%

MolecularTargets17%

Research onTobacco

& TobaccoRelatedCancers

17%

Selecting ExtraordinaryOpportunities

In 1996, NCI, with formal input from over 60 cancerscientists, educators, advocates, and community

leaders, identified four research areas of exceptionalpromise in the cancer field – Cancer Genetics,Preclinical Models of Cancer, Imaging Technologies,and Defining the Signatures of Cancer Cells – andpledged to focus increased attention and investmenton these areas for a three-year cycle.

In 1998, as this first cycle drew to a close, NCIagain approached scientific, professional, and layexperts in the cancer field to revisit the “extraordinaryopportunities” and select emerging investmentresearch areas for the next three-year cycle. NCIreceived over 250 responses from our grantees, mem-bers of our advisory boards, and advocacy groups. Wethen assessed the responses, blended related meritori-ous ideas from the initial selected extraordinary oppor-tunities, and selected three additional new investmentareas for a total of six – Genes and the Environment,Cancer Imaging, Defining the Signatures of CancerCells: Detection and Diagnosis, Molecular Targets ofPrevention and Treatment, Research on Tobacco andTobacco-Related Cancers, and Cancer Communications.

These extraordinary opportunities are different fromthe other important research areas supported by NCI;they are areas where focused efforts and increasedresources could produce dramatic progress towardreducing the burden of cancer. To qualify as extraordi-nary opportunities, these research initiatives must:

■ Respond to important recent developments in knowledge and technology;

■ Offer approaches to cancer research beyond the size,scope, and funding of our current research activities;

■ Be implemented with specific, defined investments;

■ Be described in terms of achievable milestones, with clear consequences for not investing; and

■ Promise advances for making progress against all cancers.

In addition, these investment areas will result innew extramural grant or contract awards; collaborativeefforts with other institutes, government agencies, orthe private sector; and new or expanded scientific pro-grams within NCI divisions. They promise to take us toa new era in cancer prevention and care.

Extraordinary Opportunities forInvestment Increase(dollars in thousands)

Amount

Genes and the Environment $65,036Cancer Imaging 58,700Defining the Signatures of Cancer Cells 93,000Molecular Targets 66,375Research on Tobacco & Tobacco-Related Cancers 66,000Cancer Communications 43,000

Total $392,111*

* $12,111 towards Investment areas included in Core budget level.

THE OPPORTUNITY

D ramatic scientific advances have led to new andfundamental insights into the causes of cancer.

Fueled by conceptual and technical breakthroughs,the often breathtaking pace of scientific discoveryhas engendered a tremendous sense of optimismamong cancer researchers that new avenues will befound to detect, treat, and prevent cancer. Nowhereis this sense of promise greater or the potentialimplications more profound than at the interface ofthe fields of epidemiology and genetics. By marryingthe epidemiologic approach – study of the distribu-tion and causes of cancer in human populations –with cutting-edge genetic and related moleculartechnologies, we will be able to:■ Identify genes that predispose people to cancer

(cancer susceptibility genes) whose pathways ofaction will point to previously unsuspectedenvironmental carcinogens, including thoserelated to lifestyle exposures.

■ Detect the slight to moderate elevations of riskresulting from certain types of exposures bystudying genetically susceptible subgroups.

■ Design new approaches to diagnose, prevent,and treat cancer based on an understanding ofhow genes modify and interact with environ-mental exposures.

■ Quantify cancer risks associated with gene-environment interactions, which will directindividual and public health strategies aimed at preventing and controlling cancer.

The importance of lifestyle and other environ-mental exposures as causes of cancer is unques-tionable. The pivotal role of environment isreflected in the substantial variation in cancerincidence around the world, and in the changes in risk observed among groups that migrate andbecome acculturated in the host country.Furthermore, epidemiologic research has succeed-ed in identifying a wide range of cancer-causing

exposures, including tobacco use, dietary compo-nents, sunlight, ionizing radiation, environmentalchemicals, infectious agents, obesity, exercise, hormones, and reproductive factors. Nevertheless,the causes of many cancers remain elusive. Whilebetter approaches to measuring exposures will pro-vide new insights, it is clear that the environmentrepresents only part of the equation in determin-ing who will get cancer. It also is important tounderstand cancer susceptibility. For example, whydoes one person with a cancer-causing exposure(such as smoking or infection with human papillo-mavirus) develop cancer, while another does not?

Viewing such questions through the lens ofgenetics promises to provide insights into theseapparent paradoxes. The scientific investment incancer genetics, initially focused on the intensivestudy of rare cancer-prone families, already has paidhuge dividends. These studies have opened aunique window into the basic mechanisms of can-cer, with benefits extending well beyond the rarefamilies from which they were derived. This isbecause the genes identified by these studies arealtered forms of normal genes involved in key bio-chemical chains of events (pathways) controllingfundamental cell processes. It has become clear thatthese same pathways contribute to the developmentand progression of the more common, non-heredi-tary forms of cancer. Yet even among individualswho have inherited cancer-predisposing genes, therisk of developing cancer appears to be modified byother genetic and environmental factors. There ismounting evidence that one’s genetic make-up mayinfluence susceptibility or even resistance to cancer-causing exposures. Opportunities now exist todetermine how variations in these genes combinewith environmental and other factors to inducecancer in the general population.

Three years ago, we identified cancer geneticsas an area of extraordinary opportunity. We recog-nized that to exploit fully this area’s potential – tomove it forward at the accelerated pace that accu-

Genes and the Environment1 O P P O R T U N I T Y



Opportunities

mulated knowledge and powerful technologicaladvances now permit – new initiatives were needed. Many of today’s new opportunities in thearea of genetics are a direct benefit of these scien-tific investments. For example, NCI’s CancerGenome Anatomy Project (CGAP) has resultedin the discovery of approximately 30,000 newgenes. New technologies have permitted scientiststo determine which genes are expressed (active) innormal and cancerous tissues. There has been anexponential increase in the pace of identifyinggenes that maintain the integrity of our geneticmaterial, regulate cell growth and development,and determine our response to hormones andother chemicals produced by the body as well asenvironmental agents. Related discoveries haveenabled us to characterize the function of hun-dreds of new genes and pathways. Vast public databases contain millions of entries describing genesequences, their expression in different tissuetypes, and their location in the human genome.

These advances are ushering in a new genera-tion of epidemiologic research that will lead to acomprehensive understanding of environmentaland genetic determinants of cancer. However, theexciting opportunities of this emerging field –referred to as “molecular epidemiology” – areaccompanied by enormous challenges. Populationstudies sufficiently powerful to examine the com-plex interactions of multiple genetic and environ-mental factors will involve unprecedented num-bers of participants and will require new researchinfrastructures and strategies for interdisciplinarycollaboration. At the same time, we must strive toensure that individuals will be helped, notharmed, by their knowledge of risk. What psy-chosocial, legal, ethical, and clinical issues willarise from being able to determine cancer risk?How can we help people to cope with the infor-mation and to take appropriate action? What willbe the impact on the individual, the family, andthe medical care system? These critical questionsmust be addressed with the same urgency and ded-ication with which we pursue the scientific oppor-tunities.

THE GOALS

■ Identify environmental causes of cancer usingnew epidemiologic and genetic approaches.

■ Identify genes that modify (increase ordecrease) cancer risk, including the risk result-ing from environmental exposures.

■ Integrate information on genetic susceptibilityand environmental exposures to estimate cancer risks for individuals, families, and populations.

■ Develop new strategies for cancer prevention,early detection, and treatment, building uponnew knowledge about the genetic and environ-mental determinants of risk.

THE PLAN

Objectives

1. Conduct large-scale studies of cancer inhuman populations to identify new suscepti-bility genes, environmental risk factors, andtheir interactions with one another.■ Form a consortium of investigators directing

large, prospective cohort studies of the general population.

■ Develop a network of cohorts totaling onemillion individuals under active follow-up bycoordinating studies in which genetic andexposure information is collected; add biologic specimen collections where needed.Use this resource to study gene-environmentinteractions for common cancers (e.g., breast,prostate, lung, colon, and lymphoma), particularly those related to exposures thatare best studied prospectively (e.g., diet,endogenous hormones).

■ Develop the infrastructure within existingpopulation-based cancer registries to conducta coordinated series of large-scale case-con-trol studies that include biospecimens and in-depth exposure data collection. Specifically:– Collect biospecimens and detailed exposure

information on 12,000 cancer cases and8,000 members of the general population inthe initial three years of this program.

– Use this resource to study gene-environ-ment interactions for cancers of intermedi-ate or lower incidence (e.g., pancreas,ovary, kidney, leukemia) and for studies ofthe more common tumors that requireintensive assessment of exposures and biological markers.

– Give special attention to studies of tumorswith rising incidence and mortality rates,racial and ethnic disparities, and unusualgeographic patterns.

– As appropriate, integrate population-basedcomponents of the Cancer GeneticsNetwork (CGN) and the CooperativeFamily Registries (CFRs).

■ Establish regional biospecimen repositories andhigh throughput genotyping facilities to ensurehigh quality, cost-efficient handling of biologicsamples from molecular epidemiology studies.

■ Form a network of resource laboratories todevelop and conduct specific laboratory tests(e.g., hormonal, gene expression, immunolog-ical, nutritional, toxicological) on biologicsamples from various study populations.

■ Develop informatics systems that collect,store, analyze, and integrate the vast amountsof epidemiologic, clinical, and laboratory datagenerated by large-scale studies, and safeguardthe confidentiality of all research data.

2. Develop new ways of assessing and measuring environmental exposures for use in population studies.■ Develop new epidemiologic methods for assess-

ing complex exposures over a lifetime (e.g., diet,nutrition, occupational, and other environmen-tal hazards), including computer-assisted inter-viewing techniques and improved data bases fornutritional and environmental exposures.

■ Expand the NCI’s UnconventionalInnovation Program and other funding mech-anisms to develop new techniques for usingvery small amounts of biologic samples toquantify exposures (e.g., pesticides, nutrients).

■ Expand the Phased Innovation Award andSmall Business Innovation Research programto develop non-invasive methods of collect-ing DNA for molecular studies (e.g., buccalcells) and techniques to maximize the use ofsmall quantities of genetic material.

■ Supplement ongoing research programs todevelop and validate measures of cumulativecellular genetic and molecular exposure to envi-ronmental carcinogens in non-tumor tissue.

■ Expand and supplement research programsincluding CGAP to develop and validatemolecular approaches to define in tumor cellsthe characteristic mutation pattern of DNAdamage – the “molecular fingerprint” – thatimplicates a specific carcinogen.

■ Use emerging technologies to develop molec-ular and immunologic techniques that willenable screening of large numbers of biologicsamples to identify infectious agents relevantto human cancer.

■ Work with academic centers, includingschools of public health, to train highlyskilled scientists needed to carry out molecu-lar epidemiology studies.

3. Identify and characterize gene variationsinvolved in key molecular pathways important in cancer.■ Expand the CGAP programs to identify all

cancer-relevant genes and common variants.As part of this effort:– Increase the scope of gene discovery efforts

within the Tumor Gene Index (TGI); expandthe capacity of the Genetic AnnotationInitiative (GAI) infrastructure to delineate,characterize, and validate gene variants.

– Recruit additional collaborators throughCGAP partnerships to accelerate GAI validation and confirmation efforts.

– Extend efforts to identify genetic variantsinto clinically and epidemiologicallydefined groups.

– Assess the relevance of gene variations inthe context of population studies of gene-environment interactions.

■ Extend the GAI’s efforts to define key molec-ular pathways by increasing CGAP’s capacityto assess gene expression profiles and byestablishing working groups to develop andcurate information on cancer genes and their related pathways.

■ Accelerate new technology development andapplication by expanding the GAITechnology Partners initiative and theUnconventional Innovation Program.


4. Develop new experimental models that parallel human cancer-related genes, pathways, and processes. ■ Augment the Mouse Models of Human

Cancers Consortium (MMHCC) to deriveand refine mouse models of all known humanhereditary cancer genes.

■ Generate valid mouse models based on epi-demiologic observations on genetic and envi-ronmental modifiers of cancer risk. Specifically:– Support a GAI for the mouse in a

systematic effort to identify common DNA-based genetic variants.

■ Augment the Web-based forum within theMMHCC to integrate emerging knowledgeabout cancer susceptibility from experimentalmodels and studies on human populations.

■ Support the MMHCC to discover mousegenes that modify cancer susceptibility toilluminate cancer pathways in humans. – Augment MMHCC repository support to

derive and distribute consomic and recom-binant inbred congenic mouse strains.

– Use susceptible mouse models to evaluateenvironmental factors for their potential tomodify cancer development.

– Use mouse cancer models to discover bio-markers and in vivo approaches for earlydetection and to develop and test new prevention strategies.

■ Develop and use non-mammalian organismsas models of complex interactions among thepathways and processes that contribute tocancer etiology.

5. Identify and characterize cancer-predisposinggenes in high-risk families and investigatehow the expression of these genes is modifiedby other genetic and environmental factors.■ Enhance high-risk family recruitment

through mechanisms such as the CGN,CFRs, cancer centers, and cooperativegroups. In addition, develop commonresearch tools such as family history instru-ments, model informed consent documents,and research data protection standards;expand mechanisms (e.g., Internet) to aidfamily identification and referral intoresearch programs.

■ Use these resources to initiate large collabo-rative interdisciplinary studies of high-riskfamilies to quantify cancer risk among carriersof identified major genes (e.g., BRCA1,BRCA2, APC, VHL) and to investigategenetic and environmental modifiers of risk.

■ Foster consortia of investigators to identify thegenetic basis for specific familial aggregations ofcancers that have not yet been linked to genes.

■ Expand the capability and use of the NIHCenter for Inherited Disease Research(CIDR) and other resources to acceleratefamilial cancer gene identification.

6. Develop risk assessment models that integrateinformation on genetic and environmentaldeterminants of cancer.■ Augment selected population-based studies

and clinical trials to design and validate statis-tical models that predict individual cancer riskfor specific cancers. Develop strategies to com-municate the resulting information to bothhealth professionals and high-risk persons.

■ Use these models to identify high-risk individuals for diagnostic, preventive, or therapeutic interventions.

■ Develop statistical methods and models toassess the population’s cancer burden that isattributable to susceptibility genes, specificexposures, and their interactions.

■ Use these population burden models toinform public policy.

■ Use new and existing NCI initiatives, includ-ing transition career development and estab-lished investigator awards, to train investiga-tors in clinical and population risk assessmentmethodologies.

7. Enroll high-risk individuals into clinical protocols, and conduct studies to address the clinical, behavioral, and societal issuesassociated with cancer susceptibility.■ Through the CGN, CFRs, cancer centers,

and cooperative groups, recruit high-risk indi-viduals into clinical studies to assess diagnos-tic and preventive interventions (e.g., the useof innovative breast imaging strategies or pre-ventive agents among BRCA1/2 carriers).


Opportunities


■ Expand and extend selected NCI-supportedtherapy trials to enable long-term follow-upof survivors for late treatment effects, particu-larly risk of second cancers. Include biospeci-men collections to evaluate the role of genet-ic susceptibility and other mechanisms ofcancer development.

■ Through the NCI Biobehavioral ResearchProgram, the CGN, CFRs, interagency col-laborations, and other mechanisms, conductresearch into the genetics of specific behav-ioral traits related to cancer risk (e.g., smok-ing initiation and cessation).

■ Supplement existing genetic screening pro-grams and other consortia to conduct behav-ioral research to assess the impact of predic-tive genetic testing and cancer risk assess-ment on high-risk individuals and their fami-lies, and to develop interventions for copingwith the implications of genetic information.

■ Develop and employ model procedures toprotect the confidentiality of participants inNCI-sponsored research, and prevent disclo-sure of identifying information. Implementrecommendations from the Fall 1999 NCIConference on Confidentiality, DataSecurity, and Cancer Research.

PROGRESS IN PURSUIT OF OUR GOALS

NCI has initiated a broad range of projects thatare providing many new opportunities for

studying genetic and environmental determinantsof cancer. Recent progress in several efforts ishighlighted below.■ NCI launched the Cancer Genetics Network,

a collaborative multicenter infrastructure thatwill study the genetic basis of cancer suscepti-bility and clinical outcomes; apply new geneticinformation in medical practice; and addresspsychosocial, ethical, legal, and public healthissues. In addition, NCI established theCooperative Family Registries for breast/ovar-ian and colon cancer to foster interdisciplinaryresearch in the genetic epidemiology of thesecancers.

■ The Genetic Annotation Initiative (GAI), part of the Cancer Genome Anatomy Project(CGAP), has been established to expand thearray of tools available for genetic analysis. TheGAI identifies variations in genes discoveredthrough the CGAP. Over 10,000 gene varia-tions have been discovered and in June 1999,NCI made this information available on a pub-

The year is 2000. Due largely to sun exposure, one in75 people can expect during his or her lifetime to

develop a disfiguring and potentially deadly cancer ofthe skin, mucous membranes, eyes, and central nervoussystem – malignant melanoma. In the United States,cases of melanoma have more than doubled since 1970,and the incidence of this disease is increasing dramati-cally in persons with light-colored skin in all parts of the world.

Unaware of the danger, people who were sun-worshippersin their teens and early 20s, and people doing outdoorwork without sun protection, are now, at 40 or 50 yearsof age facing the consequences of irreparable DNA damagethe sun's ultraviolet light has caused in their skin. Unlike basal cell and squamous cell carcinomas, commonskin cancers that typically can be removed surgically andrequire no further treatment, malignant melanoma is


Malignant Melanoma

5

10

15

20

1973 1976 1979 1982 1985 1988 1991 1994 1996Year

Inci

den

ce

Whites

Blacks

Melanoma Incidence 1973-1996Blacks and Whites (per 100,000 people)


Opportunities

lic Web site for investigators to validate and use. ■ The Cancer Chromosome Aberration Project,

also part of CGAP, has developed tools forcharacterizing in detail the distinct chromoso-mal alterations associated with cellular transfor-mation to malignancy. Studies recently fundedinclude a repository of bacterial artificial chro-mosomes (BACs) mapped at high resolutionacross the human genome.

■ This year, NCI funded the develop-ment of a prototype geographic infor-mation system (GIS) for breast cancerstudies. The GIS will use existing databases from Federal, state, and local gov-ernment and private sources to inte-grate environmental data on drinkingwater contaminants, ambient air pollu-tion, electromagnetic fields, ionizingradiation, pesticides, and other toxicchemicals. The system will be pilotedas part of the Long Island BreastCancer Study.

■ This year, NCI funded the MouseModels of Human Cancers Consortium, a program designed to develop and refine experi-mental models that reflect the etiology and progression of human cancer. These models

will accelerate the discovery of genes that modify susceptibility to cancer and permit thedesign and testing of new approaches for prevention, early detection, and treatment.

■ Under the auspices of the Mouse CancerGenome Anatomy Project (MCGAP), studiesare underway to investigate molecular determi-nants of cancer in the mouse for comparativestudies in human tumors. NCI will make the

MCGAP reagents publicly available insupport of efforts to identify mouse modi-fier genes involved in cancer etiology.■ The success of research in cancer

epidemiology and genetics dependscritically on our ability to safeguardthe confidentiality of genetic andother sensitive information collectedin research studies. NCI is calling for a national discussion engaging the scientific, bioethics, and advocacycommunities to address these issues,which have profound implications forthe conduct of future research. Tostimulate public discourse, NCI hasdeveloped a “white paper” on confi-dentiality, data security, and cancerresearch.

invasive – and therefore quite serious – even if it onlypenetrates the skin to a depth of less than a single mil-limeter. Many patients whose melanoma has not penetrat-ed into surrounding tissue can be cured by surgery alone.For those with more advanced melanoma, new and emerg-ing treatments hold promise for arresting the progress of the disease, or even curing it.

Drugs that enhance the immune system's response to tumorcells and drugs that attack the tumor cells are being stud-ied in patients with high-risk and metastatic melanomas.One such treatment, high-dose interferon alpha-2a, hasbeen approved by the Food and Drug Administration fortreatment following surgery for melanoma patients who areat high risk of disease recurrence.

In addition, NCI is researching new approaches to cancertreatment vaccines. In the vast arsenal of the human

immune system, there are special white blood cells thatcan infiltrate tumors, and scientists have identified withinthese cells specific molecules involved in cancer rejection.Researchers are now able to take a melanoma patient’sown tumor infiltrating white blood cells, grow or “ampli-fy” the cells, their associated genes, or gene products,and use them to treat the cancer. This individualized ther-apy, alone and in combination with the immune responsemodifier interleukin-2, has shown promising results in ini-tial studies in patients with metastatic melanoma. Otherearly studies suggest that similar new immunologicapproaches will prove useful not only in treatingmelanomas, but in treating certain groups of patientswith breast cancer, colon cancer, ovarian cancer, and lym-phomas. Such treatment, called immunotherapy, may leadto a major advance in our progress against the family ofpersistent and deadly diseases known as cancer.

To find out

more about

confidentiality

issues, visit

http://www.

nci.nih.gov/

confidentiality.

html

http://www.nci.nih.gov/confidentiality.html


Conduct population-based studies of gene-environment interactions. $20.0 M■ Create a network to coordinate prospective studies involving a total of one million participants.■ Develop infrastructure for case-control studies initially involving 20,000 participants.■ Develop repository, laboratory, and informatics infrastructures.

Assess and measure environmental exposures for use in population studies. $8.0 M■ Develop epidemiologic methods to assess complex exposures.■ Develop non-invasive DNA collection methods and technologies.■ Develop molecular measures of cumulative exposure to environmental carcinogens

in non-tumor tissue.■ Develop and validate molecular approaches to define molecular fingerprints in tumor cells

that implicate specific carcinogens.■ Develop immunologic and genotypic approaches to identify infectious agents in human cancers.■ Support interdisciplinary training programs in molecular epidemiology.

Identify and characterize gene variants in key molecular pathways. $5.0 M■ Expand CGAP programs to identify, characterize, and validate gene variants relevant to cancer.■ Extend efforts to identify cancer-related molecular pathways.■ Accelerate new technology development and application.

Develop animal/experimental model systems. $5.0 M■ Develop mouse models of human cancer-related genes.■ Develop organisms as models of gene-gene and gene-environment interactions.

Conduct family-based studies. $10.0 M■ Enhance recruitment of high-risk families into research studies.■ Initiate large collaborative studies to quantify cancer risk and to investigate genetic and

environmental modifiers of risk.■ Support consortia to study familial clusters of cancers not yet linked to genes.■ Support use of CIDR and other resources to identify familial cancer genes.

Develop risk assessment models. $2.0 M■ Develop population-based and clinical studies to design and validate risk assessment models.■ Develop methodologic approaches incorporating genetic and environmental determinants.■ Train investigators in clinical and population risk assessment methodologies.

Expand clinical research. $12.0 M■ Recruit high-risk individuals into studies assessing diagnostic or preventive interventions.■ Evaluate late effects of cancer treatment, including gene-environment interactions.■ Conduct research into the genetics of specific behavioral traits related to cancer risk.■ Assess the impact of predictive genetic testing and cancer risk assessment on high-risk

individuals and their families; develop interventions for coping with genetic information.■ Develop procedures to protect participant confidentiality.

Management and support. $3.0 M

TOTAL $65.0 M

Resources: Genes and the Environment


Opportunities

O P P O R T U N I T Y

THE OPPORTUNITY

A s recently as 25 years ago, a physician or sur-geon who suspected the presence of a tumor in

a patient had few options. Order x-ray studies todefine and localize the tumor as accurately as thepictures would permit. Schedule the patient forsurgery and examine the tumor directly, excise aportion of the unhealthy tissue for biopsy, removethe tumor if possible, and explore surrounding tis-sues to determine whether the cancer had spread.

Over the last quarter century, refinements inimaging technology have substantially broadenedthe range of medical options. Current imagingtests now provide much clearer and more detailedpictures of organs and tissues than were possiblepreviously. Imaging already has had a lifesavingeffect in detecting some early cancers. X-ray mam-mography, for example, has saved the lives ofmany women by revealing the presence of verysmall cancers before they could be detected byphysical examination. Computed tomography(CT) and ultrasound permit physicians to guidelong, thin needles deep within the body to biopsyorgans, often eliminating the need for an opensurgical procedure. CT can reveal whether atumor has invaded vital tissue, grown aroundblood vessels, or spread to distant organs; impor-tant information that can help guide treatmentchoices.

But the power of imaging technology allows usto do more than simply view structures anatomi-cally, such as visualizing bones, organs, and tumorsin the body. Functional imaging – the visualiza-tion of physiological, cellular, or molecularprocesses in living tissue – allows us to see suchthings as blood flow, oxygen consumption, or glu-cose metabolism in real time, as they take place inliving cells of the body. As we gain a better under-standing of the fundamental nature of cancer, cel-lular and molecular imaging will be a key tool intranslating this knowledge into better ways of

diagnosing, treating, and preventing the disease.Imaging can identify the kinds of molecular struc-tures/receptors that cover the surface of a tumor,information that potentially can predict how itmay behave and respond to certain treatments. Or, by providing a picture of glucose utilization intumor cells, imaging can demonstrate – withoutthe need for a biopsy – how a tumor is respondingto a recently administered treatment.

And seeing how the processes and pathwaysinside a cell change as the cell transforms fromnormal to cancerous will allow us to detect thischange in people earlier in the cancer process,perhaps before a tumor has even had the chanceto become fully malignant. Eventually we expectto be able to visualize the actual molecular signa-tures of a cancer. We will be able to tell, in theradiology suite of a hospital, which genes are beingexpressed in a person’s cancer, and we will be ableto translate this information directly into bettermanagement of the disease. In other words, theability to detect, through imaging, the molecularchanges associated with a tumor cell will vastlyimprove our ability to detect and stage tumors,select appropriate treatments, monitor the effec-tiveness of a treatment, and determine prognosis.

The potential of imaging to improve cancertreatment extends well beyond using imaginginformation to help select effective treatments orpreventives. For example, combining precise imaging techniques with radiation sources andhigh performance computing is significantlyimproving our ability to shape radiation treat-ments to the tumor’s three-dimensional contours.In principle, imaging techniques can be interfacedwith other tumor-killing approaches – toxic chem-icals, gene therapy, heat, and cold – to more pre-cisely guide tissue destruction at the tumor site.Being able to distinguish between cancerous andnormal tissue and deliver treatments only to dis-eased tissues in a minimally invasive way willpotentially minimize surgical trauma, shorten

Cancer Imaging 2


recovery time, and reduce health costs. Parallel developments in image enhancement

agents are improving our ability to capturechanges in the biochemical makeup of cells andother living structures. Enhancement agents con-tribute to image formation in three ways. Theymay localize in certain body organs or structures(anatomic localization); they may attach to specif-ic molecules in the body (receptor localization); orthey may become activated by certain biochemicalor physical conditions, such as the presence of aspecific enzyme or low oxygen concentration inthe cell (activatable agents). We anticipate thatcontrast agents of the future will be able to revealthe functional characteristics of tumors that deter-mine clinical behavior and response to therapy.

In imaging, as elsewhere in cancer research,animal models of cancer will make possible certainkinds of studies that are difficult or impossible toperform in people. In addition to learning moreabout cancer, work with animal models can enableimaging technology improvements that then canbe applied in the clinic. Imaging permits repetitiveobservations of the biological processes underlyingcancer growth and development, and the level ofresolution with some imaging modalities is nowapproaching the size of individual cells. Imagingalso can help assess the effectiveness of newinstruments, and animal studies will be crucial indeveloping a new generation of clinically usefulimaging agents to assess drug effects in patients.

Although it seems clear that better imagingtools will improve patient care, we need betterways of measuring that improvement. In evaluat-ing new therapies, a cure or prolonging thepatient’s life are often important measures of effec-tiveness. For diagnostics, however, these measuresare relatively insensitive. The problem is that survival is a global reflection of all diagnostic andtherapeutic interventions that a patient experi-ences; it often is difficult or impossible to ascribeimprovements in survival to a particular diagnostictest. More appropriate measures of effectivenessmight include, for example, greater efficiency oftesting, less cost, fewer hospital days, less morbidi-ty, and the need for less extensive or disfiguringtreatment. In short, we need improved methodolo-gies to assess the ultimate value of diagnostic tests.

Three years ago, NCI recognized the greatuntapped potential that imaging technology holdsfor cancer and identified it as an area of extraordi-nary opportunity. With this designation, we begana three-year effort aimed at significantly advancingimaging to more fully exploit its promise for can-cer research and care. By establishing an ImagingWorking Group, we stimulated constructive com-munication among experts from diverse disciplineswho have advised NCI about how we can quicklyand effectively move imaging research forward.The efforts of this group helped us define researchneeds and opportunities. In the past year, welaunched a national network to evaluate diagnos-tic imaging technologies. We also have establishedseveral small-animal imaging research centers.

Still, we have much important work to dobefore the full promise of the imaging sciences isrealized for cancer. Having laid the groundwork,we now will target tangible improvements in can-cer detection, diagnosis, and treatment – resultsthat will provide real clinical benefits for peoplewith cancer and those at risk.

THE GOALS

■ Develop and validate imaging technologies andagents (e.g., probes, radiocontrast agents) thathave the sensitivity to detect precancerousabnormalities and very small cancers.

■ Develop imaging techniques that identify thebiological properties of precancerous or cancer-ous cells that will predict clinical course andresponse to interventions.

■ Develop minimally invasive imaging technolo-gies that can be used in interventions and inassessing treatment outcomes.

■ Foster interaction and collaboration amongimaging scientists and basic biologists, chemists,and physicists to help to advance imagingresearch.

■ Create infrastructures to advance research indeveloping, assessing, and validating new imaging tools, techniques, and assessmentmethodologies.

THE PLAN

Objectives1. Accelerate development of clinically useful

technologies for detecting malignant and precancerous cells and for visualizing theirfunctional characteristics.■ Expand the number of In Vivo Cellular and

Molecular Imaging Centers. (See Progresssection for description)

■ Expand the Small Animal Imaging ResourcesProgram to improve access to researchers test-ing new approaches to diagnosis, treatment,and prevention in animal models of cancer.NCI will foster collaborations between thisprogram and the Mouse Models of HumanCancers Consortium.

■ Support multidisciplinary centers of expertiseto develop optical technologies and performclinical feasibility tests of instruments able tovisualize epithelial tissue at risk for commoncancers and recognize the optical signaturesof precancerous abnormalities.

2. Develop, synthesize, validate, and distribute to the research community novel imaging agents. ■ Create a program similar to NCI’s Rapid

Access to Intervention Development initia-tive (designed to accelerate the movement ofnovel interventions from the laboratory tothe clinic) for imaging agents. NCI will, on acompetitive basis, synthesize, test, and dis-tribute probes that image the physiologicaland functional status of tumor tissue in thehuman body.

■ Establish a publicly available data base ofagents available to the research community,together with information on their properties.

3. Expand and improve clinical studies of imaging modalities and image-guided interventions.■ Establish centers for developing and clinical

feasibility testing of technologies enablingminimally invasive, image-guided therapy forlocalized malignancies (e.g., brain, breast,prostate).

■ Enable collaborations between the clinicalcooperative groups and the DiagnosticImaging Network (see Progress section fordescription) for definitive testing of minimal-

ly invasive, image-guided interventions thatappear promising in early feasibility studies.

■ Expand the Diagnostic Imaging Network topermit it to develop a full menu of clinicaltrials relating to all major cancers.

■ Develop methodologies to assess the medicalvalue of diagnostic tests in clinical trials.Support the full development of outcomesresearch as applied to the evaluation of imag-ing diagnostics.

4. Integrate molecular and functional imagingtechnologies into drug development and earlyclinical trials. ■ Support the development of in vivo and

clinical imaging research tools for assessingthe biologic effect of cancer drugs on theirintended target or pathway. (See MolecularTargets)

5. Establish information archives and reposito-ries needed by the research community. ■ Establish data banks of standardized digital

images associated with known clinical outcomes.

■ Provide resources to develop and test imageprocessing and analysis algorithms on thesestandardized data sets.

6. Provide innovative imaging equipment to theresearch community for limited scale feasibility testing.■ Establish a competitive program in which

innovative equipment prototypes developedin industry or academia will be provided toselected academic institutions for feasibilitytesting, in close collaboration with the developer.


Over the past year, NCI launched several excit-ing new initiatives and achieved important

progress in ongoing programs. The followingdescribes some of our new programs and activitiesas well as the progress made in programs alreadyunderway. ■ Advances in both structural and functional

imaging technologies have produced remark-able tools for understanding, detecting, anddiagnosing cancer. Yet the power of these tools


Opportunities

could be amplified appreciably if advances inimaging technology could be merged with themyriad new discoveries in cancer-related genesand proteins. A scientific gulf still existsbetween basic scientists who discover new can-cer genes and intracellular pathways – any ofwhich could serve as a diagnostic or therapeutictarget – and imaging scientists who focus onnon-invasive approaches to transform these dis-coveries into a greater understanding of cancer.To narrow this gap, NCI will award two tothree grants in the coming year to support In Vivo Cellular and Molecular ImagingCenters (ICMICs). ICMICs will facilitateinteraction among scientists from a variety offields to conduct multidisciplinary research oncellular and molecular imaging. Because theintegration of this breadth of expertise is still inits early stages, the NCI also will award six pre-ICMIC planning grants. The pre-ICMIC plan-ning grants will provide time and funds forinvestigators and institutions to prepare them-selves, organizationally and scientifically, toestablish an ICMIC.

■ Digital mammography is considered one of the most promising technologies for use inlarge- scale screening programs to improve early breast cancer detection. To advance the state-of-the art in digital mammographydisplays and workstation design, NCI has setaside funds to encourage studies that focus on

research and development in critical areas tomake digital mammography a more usefuldevice in clinical settings.

■ Small animal models, particularly geneticallyengineered mice, are powerful discovery tools,but we have yet to capitalize fully on theirpotential in cancer research. NCI will fund fourto five Small Animal Imaging ResourcePrograms this year. This initiative will supportactivities to develop and apply a wide variety ofimaging modalities that focus on functional,quantitative imaging. Quantitating image datafor small animals will lead the way to quantita-tive methods that can be applied in humans.

■ Preclinical models of human cancer can bevaluable tools for developing and testing newtherapeutic, preventive, early detection, anddiagnostic imaging strategies. NCI will developand use a Preclinical Models Imaging Forum(a mechanism that will include meetings and aWeb site) to link the expertise of participantsin the Mouse Models of Human CancerConsortium, imaging technique developers andusers of the small animal imaging centers, theDiagnostic Imaging Network, investigatorsusing imaging techniques to observe patients,and investigators who use model systems otherthan mice. The information generated throughthis forum will be helpful for designing andtesting imaging techniques to detect humancancers and in developing and validating new



How Can Spiral CT Improve Early Detection of Lung Cancers?

Finding lung cancers early is believed to be a missingkey to combating this deadly disease – the leading

cause of cancer death for men and women in the UnitedStates. Yet despite intensive research, a reliable screen-ing technique for early detection of lung cancers haseluded discovery. Now, however, advances in imagingtechnology have led to the development of a screeningtechnique, spiral computerized tomography (spiral CT),that may prove to be the first screening method to find some of these cancers early and reduce lung cancer deaths.

With spiral CT, the entire lungs, from the neck to thediaphragm, can be scanned in less than 20 seconds – asingle breath-hold. Rapid scanning improves the detectionof smaller lesions since they are not moving in and out ofthe field of view due to breathing; moreover, rapid scan-ning minimizes radiation exposure. Preliminary studies ofspiral CT have shown promise in detecting small cancers.For example, adenocarcinomas, the most common lungcancer, can be detected more readily with spiral CT thanwith standard chest x-ray. However, this technology maybe less useful for detecting central airway tumors, such as

preclinical models.■ Before new or refined imaging tools can be used

as cancer diagnostic instruments, they must beevaluated for their safety and effectiveness. InMarch 1999, NCI funded the DiagnosticImaging Network to bring together imagingexperts from around the Nation to perform abroad spectrum of multi-institutional clinicaltrials on diagnostic imaging tools relat-ed to cancer. The Diagnostic ImagingNetwork will establish collaborationswith NCI Cooperative Groups to expe-dite the integration of diagnostic imag-ing technologies into clinical trialsaimed at assessing new therapies.

■ Improved imaging techniques canenable clinicians treating prostate can-cer to accurately localize and stage atumor, information that can be usefulfor choosing treatments. NCI has setaside funding to launch a new initia-tive aimed at developing non-invasive imagingtechnologies for the localization, biopsy, andminimally invasive treatment of prostate can-cer.

■ New drug discovery programs are producing anever increasing number of molecules for investi-gation, in turn stimulating a need for researchthat integrates imaging techniques into preclin-ical and clinical studies to assess newly devel-

oped therapeutic agents. NCI has set aside fundingfor the development and application of labeledtherapeutic agents as compounds for imagingstudies and imaging agents that serve as metabol-ic markers of response to newly developed thera-peutic agents.■ NCI, the National Electrical Manufacturers

Association, the FDA, and the Health CareFinancing Administration are collaborat-ing to develop partnerships with the imaging industry.■ To stimulate the discovery, develop-

ment, and advancement of highlyinnovative new areas of imaging sci-ence, NCI has made availableExploratory/Development Grants forDiagnostic Cancer Imaging. Thesegrants are designed to provide investi-gators with the initial resourcesrequired to accomplish feasibility andpilot testing of innovative ideas. Someof these feasibility studies will help

generate new research programs in previouslyunexplored areas. This ongoing program alreadyhas been used to fund studies in a wide varietyof imaging areas, including new MRI technolo-gy to diagnose head tumors, and a systememploying both MRI and ultrasound in minimally invasive detection of prostate abnormalities.


Opportunities

squamous cell carcinomas, and very rapidly growing carci-nomas, such as small cell lung cancers.

NCI is funding clinical trials to determine the size andtypes of abnormalities that can be detected by spiral CT.But many lesions detected with this technology may notbe malignant. Therefore, to avoid invasive, potentiallydangerous biopsy procedures such as open lung surgery,we must consider carefully how we will evaluate theabnormalities found with spiral CT. Two technologies areavailable to aid in diagnosis: high-resolution CT, which

helps to distinguish between cancerous and non-cancer-ous tissue, and positron-emission tomography (PET),which shows the differing uptake of radioactive isotope“tracers” in benign growths and malignant tumors. Other diagnostic techniques are being studied. But thepotential physical and psychological complications arisingfrom evaluation of what eventually is found to be benigndisease must be recognized and addressed. NCI will alsofund studies to assess the benefits and risks of routinelung cancer screening.

For information

on the

Diagnostic

Imaging

Network visit

http://www.

acrin.org

http://www.acrin.org/


Resources: Cancer Imaging

Develop clinically useful technologies for detecting malignant and precancerous cells. $27.2 M■ Fund 2 Centers and 8 four-year planning grants for In Vivo Cellular and Molecular Imaging

Centers. ■ Support 10 additional Small Animal Imaging Resource Programs.■ Support 4 multidisciplinary Centers of Excellence for Optical Technologies.

Develop, synthesize, validate, and distribute novel imaging agents. $4.0 M■ Create a RAID-like program for imaging agents – fund 3 to 6 agents.■ Establish a publicly available data base of agents.

Conduct clinical trials of imaging modalities and image-guided interventions. $16.5 M■ Establish 4 centers for development and clinical feasibility testing of image-guided therapy

for localized malignancies.■ Support collaborations between clinical cooperative groups and the Diagnostic Imaging Network.■ Expand the Diagnostic Imaging Network.■ Develop methodologies to assess medical value of diagnostic tests in clinical trials.

Integrate molecular and functional imaging technologies into drug development. $.0 M(Budgeted in the Molecular Targets Opportunity.)■ Support development of in vivo and clinical imaging research tools for assessing drug effects

on intended targets.

Develop information archives and repositories. $1.5 M■ Establish data banks of standardized digital images associated with known clinical outcomes.■ Develop and test image processing and analysis algorithms on standardized data sets.

Evaluate innovative imaging equipment. $7.5 M■ Establish a competitive program for feasibility testing of innovative prototypes.


TOTAL $58.7 M

THE OPPORTUNITY

In the 19th century, the light microscopeopened a new frontier in the study of disease

by opening a window on the inner workings of thecell. The science of pathology – the branch ofmedicine that deals with the essential nature ofdisease – expanded to include the study of struc-tural changes in cells. For the first time, diseasecould be linked to visible, recognizable changes in the cells of the body.

At the cusp of the 21st century, new molecular-based technologies are bringing us to a similarepiphany. These new technologies are enabling usto identify features of individual cells in waysunimagined by our 19th century predecessors. Forexample, all cell types, depending on their func-tions, have unique, identifiable “signatures” – spe-cial characteristics such as which genes are activeand what proteins or other cellular products aremanufactured by the cell. Our new technologiesare enabling us to read and understand those sig-natures. We have learned that during the transfor-mation of a normal cell to a cancer cell, the signa-ture changes, and that change becomes a signal ofthe presence of cancer.

Further, we have learned that cells surroundingthe incipient tumor may also undergo changesindicating that cancer is present. For example,tobacco-induced molecular changes in the mouthmay predict the risk of developing lung cancer,and cancers of the urinary tract may be signaled bycancer cells that are “shed” in the urine. Readingthe signatures of these easily accessed cells mayenable us to develop simple, non-invasive tests tofind cancers located deep within the body.

The implications of these findings are profound.By reading cellular signatures accurately, we maybe able to detect and diagnose cancers before theyhave had a chance to invade nearby tissues. Infact, with the tools we are developing, a singledrop of blood from a patient’s finger may be all

that is needed to find a cancer, assess the threat itposes by comparing its traits to profiles in an on-line library of tumor characteristics, choose thebest possible treatment, and monitor the patient’srecovery. By assessing the meaning of individualchanges in the cell’s signature, we will be able todetermine which cancers are most likely toprogress and which are less likely to do so – adilemma that confronts, for example, doctorstreating patients with prostate cancer – therebyavoiding the consequences of unnecessary treat-ment. By studying the sequence of changes a cellundergoes as it transforms from normal to cancer-ous, we will gain important insights into the etiol-ogy of the disease. And by applying what we havelearned, we will be able to identify new targets, atthe molecular level, for effective prevention andtreatment. (For more on this exciting area ofscientific opportunity, see page 57.)

“Defining the Signatures of Cancer Cells” wasfirst identified as an area of extraordinary scientificopportunity in 1996, and it continues to be anarea rich in scientific promise today. For example,we now are in a position to learn new ways tocharacterize tumors more efficiently – that is, todetermine which genes are active and inactive,and the levels of specific proteins that are presentin a particular tumor. Such “molecular fingerprint-ing” will greatly enhance the specificity of cancerdiagnosis by allowing us to differentiate amongtumors at the molecular level, and will enable usto devise treatments targeted at cellular subtypesof different cancers. We can now use changes inmolecular signatures to help us identify infectiousand environmental agents that may be responsiblefor the development or progression of a tumor. Inaddition, while many of our previous efforts havecentered on identifying genes involved in cancer,we are very interested in learning more about thefunctions of the proteins produced by these genes.Finally, there has been a gap between the identifi-cation of preclinical tumor changes, early evalua-

Defining the Signatures of Cancer Cells: Detection and Diagnosis

3O P P O R T U N I T Y


Opportunities

tion of new identification techniques, and theirclinical application. We now have the opportunityto synthesize these disparate findings into a bodyof knowledge that will translate into real healthbenefits. Our ultimate goal is to push back thedetection and diagnosis of cancer to the earlieststages, thereby offering the potential to focusintervention efforts at preventing overt disease,rather than at treatment.

Clearly, we have made substantial progress.However, much remains to be done if we are totake full advantage of the opportunities in thisarea. The diagnostic value of molecular-basedmethods must be confirmed and their practicalbenefits established against the background ofconventional medicine. New technologies must bedeveloped, and new preclinical models must becreated and validated to establish our findings.Finally, it is crucial that we develop the sophisti-cated computer systems, data bases, and statisticalmethods needed to integrate the complex informa-tion being generated by the new technologies withthe biologically relevant data. In this way we willbe able to validate the predictive value of the newapproaches.

THE GOALS

■ Complete the molecular catalogue of cancer bycharacterizing the molecular profiles of precan-cerous and cancer cells at all stages of clinicaldisease, associated host cells, and surroundingtissue and body fluids.

■ Develop improved methods for detecting pre-cancerous lesions and cancers at their earlieststages, when cure is most possible.

■ Develop a new taxonomy for cancer based onthe molecular signatures of cells and use it todevelop improved strategies for cancer diagnosisand prognosis.

■ Develop preclinical models that reflect themolecular basis of human cancer etiology andprogression; use the models to inform thedesign of new molecularly based approaches forearly detection, diagnosis, prognosis, and treat-ment of cancer, and to test and refine theseapproaches.

■ Develop integrated technologies to detectdefined molecular signatures that predict canceroccurrence or progression and provide a seam-less interface with intervention.

THE PLAN

Objectives1. Continue to characterize the molecular pro-

files of precancerous and cancer cells at allstages of clinical disease, associated host cells,and surrounding tissue and body fluids. ■ Complete the Tumor Gene Index of genes

expressed in cells at all stages of tumor development.

■ Enhance the Director’s Challenge to establishmolecular profiles of human cancer anddevelop molecular classification schemes forall human cancers.

■ Fund the development of data bases and ana-lytic tools for comprehensive molecularanalysis.

2. Establish and make available tissue resourcesto maximize the practical application ofmolecular signatures to problems in cancer. ■ Establish a national tissue resources system

for all major cancers, including cancers of thelung, breast, prostate, colon, head and neck,brain, soft tissue, blood, bone, the gynecolog-ic and genitourinary systems, and childhoodmalignancies.

■ Develop tissue arrays and implement a systemfor distributing tissue and tumors.

■ Publicize the existence and capabilities of tis-sue resources to the research community.

■ Partner with the advocacy community to develop a public education program on issues surrounding tissue donation for research.

3. Develop and deploy a robust informatics system for molecular pathology.■ Establish pathology standardization and

agreement on common data elements.■ Develop query and search capability for the

national tissue repositories.■ Provide automatic encryption features for

personal identifiers associated with tissueresources.



Opportunities

■ Establish linkages to population data bases,such as SEER and other registries, to aid inacquiring outcome and follow-up information.

4. Create a classification system for cancer andpre-cancer based on the molecular signaturesof cells; use it to model improved approachesto early detection, diagnosis, and prognosis.■ Initiate a “Director’s Challenge” to fund

consortia to identify molecular signatures of preneoplastic lesions associated with cancer development.

■ Fund the development of tissue repositories of precancerous lesions.

■ Support the development of standards forcorrelating molecular and pathologic criteriaused to define stages of human cancer development.

■ Expand the Early Detection ResearchNetwork to expedite the discovery, valida-tion, and development of new early detectiontests for all major human cancers.

■ Support the development of high throughputtechnologies for isolating and enriching cellsshed in body fluids.

■ Support the development of high throughputassays for the molecular characterization ofproteins and for detecting informative mark-ers in body fluids.

5. Validate molecular signatures for their poten-tial value in cancer diagnosis and prognosis,and in predicting intervention response.■ Create a Diagnostics Validation Network to

provide the research community with ameans to evaluate and validate signatureswith possible diagnostic value. Establish link-age to clinical information (i.e., pathology,histology, treatment response, stage, andgrade) to establish surrogate molecular end-points for application in cancer preventionand treatment studies.

■ Provide supplemental funding to groups conducting prevention and therapy studies to evaluate biomarkers for their ability to predict response to therapeutic and preven-tion interventions.

6. Develop preclinical models that reflect thegenetic and molecular changes implicated inhuman cancer etiology and progression.■ Accelerate the Mouse Cancer Genome

Anatomy Project to define the molecularanatomy of mouse cancer models.

■ Provide funds to validate mouse models ofhuman cancer by systematic analysis and phenotyping.

■ Develop Mouse Models Application Funds totest early detection, diagnostic, imaging, pre-ventive, and therapeutic interventions inmouse models.

■ Fund Phased Innovation Awards to developnew tissue, cellular, and computational mod-els of cancer.

7. Support the development of new technologies. ■ Expand the Unconventional Innovations

Program to develop biosensors of human can-cer and cancer development.

■ Fund an Unconventional Innovation AccessProgram to apply technology discoveries toclinical testing.

■ Initiate a collaboration with the NationalAeronautics and Space Administration(NASA) to develop minimally invasivemolecular biosensors.


The past several years have seen an explosion ofdiscovery in this area. NCI’s new and ongoing

initiatives include: ■ The Institute’s flagship program for molecular

discovery is the Cancer Genome AnatomyProject (CGAP). CGAP’s overall goal is todetermine the complete profile of expressed(active) genes in normal, precancerous, andcancer cells, with the aim of making it possibleto recognize all major steps of tumor develop-ment. Thus far, we have established the plat-form for building the complete molecular cata-logue of cancer. Initially, we focused on cellsthat directly give rise to tumors and placedemphasis on five major types of cancer. Nowthat the necessary infrastructure has been estab-lished, we are positioned to examine a muchwider variety of cancers and to extend our dis-

covery process to include cells that play keysupporting roles in cancer development, such asthe cells that form the tiny blood vessels thatfeed tumors, cells that metastasize and the tis-sues that support those metastases, as well asbody fluids that might contain early indicationsof cancer development. This new informationwill greatly enrich our molecular catalogue ofcancer and make it even more useful to theresearch community.

CGAP is composed of five initiatives. The most established of these is the Human TumorGene Index (TGI). Its primary goal is to iden-tify the genes expressed during the develop-ment of human tumors. Data from the CGAPhave been used to discover approximately30,000 new human genes. Other components ofCGAP include the Mouse TumorGene Index, the Cancer ChromosomeAberration Project, the GeneticAnnotation Initiative, and MolecularProfiling. Each of these is described ingreater detail on the CGAP Web site.

■ NCI is creating a multi-institutionalEarly Detection Research Network todevelop sensitive and specific tests forthe earlier detection of cancer. TheNetwork will link centers of expertisein tumor biology, diagnostic technologies, andclinical trials methodology in academia andindustry to develop high throughput assays suit-able for clinical application. To expedite thediscovery and development of more sensitiveand specific markers for early disease, NCI alsowill establish links between Network activitiesand programs in academia and industry.

■ In 1998, the NCI Director issued his Director’sChallenge: Toward a Molecular Classificationof Tumors, a challenge to the research commu-nity to revolutionize the classification of humantumors. Traditionally, tumor classification hasbeen based on morphology, or the tumor’s struc-ture. But morphological classification alonedoes not always accurately predict biologicalbehavior, treatment response, or prognosis. Weanticipate that the research community will riseto this challenge and discover new ways to

combine technological advances in moleculardetection with rapidly advancing knowledge oftumor biology to provide a more clinically pre-dictive and useful tumor classification system.

■ Success in developing molecular diagnosticsdepends on the availability of specimen banksfor tissue analysis. NCI has several programsdesigned to collect and disseminate tissue, suchas the Cooperative Breast Cancer TissueResource. NCI also will develop a nationalprostate cancer tissue resource. In addition,NCI sponsors the Tissue Expediter, a scientistwhose role is to identify sources of human tissuespecimens and to help researchers locate thetissue and related data they need.

■ Models that truly reflect the behavior of humancancer and its response to preventive and ther-

apeutic maneuvers would profoundlyimprove our ability to understand theprocess of malignant transformation, andcould enhance our ability to evaluate arange of biomarkers prior to their clinicalapplication. To meet the need for animalmodels in a variety of settings, NCI issoliciting applications for establishing aconsortium that will develop and vali-date mouse models for human cancer.■ New technology development is key to

success in this area. Many new tech-nologies will be supported through NCI’sPhased Innovation Award, developed last yearto support technology research from the evolu-tion of innovative concepts, through feasibilitytesting, and ultimately to subsequent full-scaledevelopment. In its first year, this mechanismalready has reduced significantly the time lagbetween the review process and applicationfunding, and is expected to continue accelerat-ing the pace of technology development forprofiling molecular characteristics of preneo-plastic cells. A similar award, the PhasedTechnology Application Award, has been created to support the pilot application ofinstrumentation, techniques, and analytic tools (e.g., computer software) relevant to researchon the molecular biology of cancer.


For more CGAP

information,

visit

http://www.

ncbi.nlm.nih.

gov/CGAP

http://www.ncbi.nlm.nih.gov/CGAP/


Opportunities

Resources: Defining the Signatures of Cancer Cells

Characterize the molecular profiles of precancerous and cancerous cells. $16.0 M ■ Complete the Tumor Gene Index.■ Enhance Director’s Challenge to establish molecular profiles of human cancer and develop molecu-

lar classification schemes for all human cancers.■ Develop data bases and analytic tools.

Establish and make available tissue resources. $7.0 M■ Establish and promote a national system.■ Develop public education materials about tissue donation for research.

Develop and deploy molecular pathology informatics system. $3.0 M■ Establish standardization and common data elements. ■ Provide automatic encryption features.■ Establish linkages to population-based data resources.

Create new classification system for cancer; use it to model improved approaches to detection, diagnosis, and prognosis. $20.5 M■ Initiate a Director’s Challenge to identify molecular signatures of preneoplastic lesions. ■ Expand the Early Detection Research Network.■ Develop repositories, assays, and new technologies.■ Develop standards for correlating molecular and pathologic criteria used to stage cancer.

Validate potential molecular signatures. $16.0 M■ Create Diagnostics Validation Network.■ Provide supplemental funding to groups to evaluate biomarkers.

Develop preclinical models. $15.0 M■ Accelerate the Mouse Cancer Genome Anatomy Project.■ Develop Mouse Models Application Funds to test early detection, diagnosis, prevention

and treatment interventions.■ Develop new tissue, cellular, and computational models of cancer.

Support technology development. $11.5 M■ Expand the Unconventional Innovations Program to develop biosensors.■ Fund an Unconventional Innovation Access Program to apply discoveries to clinical testing.■ Collaborate with NASA to develop minimally invasive molecular biosensors.


TOTAL $93.0 M

CANCER OR PRECANCEROUS LESION

1 Define Molecular Signatures: Identify cell pathways important to cancer

2 Identify Molecular Targets: Target pathways critical to cancer development and progression

3 Develop High-Throughput Screens for High-Priority Targets: Develop assays to detect effects of drugs on targets

4 Screen Thousands of Chemicals and Biologicals: Use high-throughput assays to identify agents that hit priority targets

5 Identify the Best Drug Candidatesfor Preclinical Development

6 Laboratory Testing and Preparing for Human Trials: Turn acandidate into a drug suitable for clinical testing

7 Phase I Clinical Trial: Study safety, toxicity, pharmacology

8 Phase II Clinical Trial: Study anti-cancer effect

9 Phase III Clinical Trial: Study efficacy compared to standard approaches

10 Widespread Clinical Use


The Path to a New Cancer Drug

The pathway to the development of a new treatment orpreventive drug begins at the cell. All cells have uniquesignatures composed of all the genes that are active, pro-teins that are secreted, processes that are followed, andpathways that are present. A cancer cell’s signature differsfrom that of a normal cell; different genes are active or

inactive, for example, or different pathways may be pres-ent. Certain components of a cancer cell’s signature –genes, pathways, or patterns of behavior – may be espe-cially vulnerable to the action of treatment or preventiveagents. These components are the molecular targets atwhich treatments or preventives can be aimed.

In developing a new anti-cancer drug, scientistsmust first identify and understand the cell’s true signature before choosing the molecular target (2).

Once a target is identified, we can screen thousands of agents (3,4) in the laboratory to determine which agentsare effective against the target (5).

Extensive laboratory testing of the most promis-ing agents follows, beginning in the test tube,then moving to living systems such as mice (6).

If an agent continues to show promise, it makes the next steps to testing in humans (7-9) (see page 27 for an explanation of clinical trials).

Finally, if the agent is proven safe andeffective, it becomes a regular part ofour arsenal against cancer (10).


Opportunities

Molecular Targets of Prevention and Treatment 4O P P O R T U N I T Y

THE OPPORTUNITY

Our systematic search for drugs to combat can-cer began about 60 years ago. During most of

this search, our understanding of cancer has beenlimited by technologies available at the time – themicroscope enabled us to see the structure of thecancer cell, but our ability to discern the oncenormal features and internal pathways that hadbecome corrupted was incomplete. As a result, ourtechniques for identifying drugs to prevent or treatcancer were rate-limiting, involving tests thatmeasured inhibition of cancer’s development or itsgrowth in animals or test tubes. Despite these lim-itations, scientists have identified drugs that, aloneor with surgery, can cure some cancers in peopleand can significantly ease symptoms in others.

Yet anyone who has ever undergone treatmentfor cancer – or watched a loved one undergo treat-ment – knows that our ability to treat the diseaseleaves much to be desired. Most of the commontumors of adults – the ones that cause most of thesuffering and death from cancer – do not respondwell to the treatments available today. And evenwhen these treatments succeed in shrinkingtumors or eliminating them from the body, theycan cause a variety of short- or long-term sideeffects that can have a devastating impact on apatient’s quality of life.

Many of the serious side effects of cancer treat-ments stem directly from their non-selectivenature. Until recently, we were unable to detectthe differences between the molecular features ofnormal and cancerous cells, and thus, a compoundthat inhibited the growth of a tumor cell alsoinhibited the growth of a healthy cell. This iswhat causes many of chemotherapy’s most severetoxic effects. However, drugs that target themolecular differences between tumor and normalcells – the altered genes or proteins or the corrupt-ed pathways – would be less toxic and more effec-tive than the drugs we currently have.

The situation for prevention is similar. Therecent findings that the anti-estrogen tamoxifencan reduce the risk of invasive breast cancer sug-gests that cancer prevention is a realistic possibili-ty. If we know the precise molecular steps thatcharacterize premalignant change, we can attemptto find agents that reverse these changes or pre-vent next steps critical to the full development ofcancer from occurring. This new generation ofchemopreventives will be optimized and mademore efficient by clinically testing the effect of apreventive on its intended target.

Until recently, scientists working to discovereffective prevention and treatment agents havefaced a formidable barrier: not knowing preciselywhat cancer is. No longer is this the case. Withthe evolution of molecular biology and the emer-gence of new technologies, we are gatheringremarkable knowledge about the nature of a can-cer cell and the molecular changes that occur dur-ing a tumor’s development. The extraordinaryopportunity before us – to discover and exploitmolecular targets for cancer prevention and treat-ment – arises from the convergence of scientificadvances in several areas.

Cancer BiologyWe continue to make astounding strides in ourunderstanding of how molecules and pathways inpremalignant or fully malignant cells differ fromtheir normal counterparts. This new knowledge isenabling us to understand and classify humantumors in terms of molecular changes and also hasgiven us a new strategy for cancer drug discovery.Today, every difference between cancerous andnormal cells is not only a biological fact or a pointof interest to the biochemist, it is a potential tar-get of opportunity for drug discovery.

Synthetic ChemistryTraditionally, the chemicals used in anti-cancerdrugs have come from nature – from tropical rain

forests or organisms in the sea or the soil. Usingrecently developed techniques, chemists now areable to create in the laboratory enormously diversecollections of compounds. Now, both naturallyand synthetically derived chemicals can bescreened for possible anti-cancer effects. The ability to test the effectiveness of large numbers of structurally diverse compounds – using highlyinformative cancer-relevant techniques thatexploit our knowledge of cancer biology – is now a reality.

Biosynthetic ChemistrySynthetic chemists have long been able to manip-ulate small molecules to produce useful medicines.The recent biotechnology revolution has clearedthe way for biochemists to mix and match genesto design synthetic proteins. Changing proteins incells is an important breakthrough, since proteinsform the “messages” that make up communicationpathways that determine a cell’s healthy or aber-rant behavior. Historically, scientists have beenunable to alter these messages since they only hadaccess to proteins produced naturally within cells.Now scientists can change the messages sent byprotein molecules, creating a whole new class ofdrugs to be tested for anti-cancer activity.

High Throughput ScreeningOver the past decade, advances in biotechnologyhave made it possible to devise highly sensitive,highly efficient tests for virtually any biologicalprocess. These tests, or “smart” assays, can be usedmany different ways. For example, they can beused to screen cell lines and tissues for the pres-ence of particular genes, proteins, or entire path-ways – an essential step in identifying the chain ofevents involved in every stage of cancer develop-ment. These assays also can be used to screenpotential drugs for anti-cancer effects; thousandsof compounds can be screened in this mannereach week. Moreover, these assays can be per-formed on a micro scale with tiny quantities ofmaterial, using computer-driven robots to maxi-mize efficiency.

Medical ImagingUntil now, imaging has been used in cancerresearch and care to gain information about theoccurrence, size, and location of tumors.

Refinements in imaging technology are allowing usto watch molecular processes within the cell unfold,as they occur, with unprecedented vividness andaccuracy. Imaging techniques are being developedto tell us not only the location of a tumor but thekind of molecules it contains and how its biochemi-cal pathways work. Further advances will have aprofound impact on the testing of potential cancerinterventions. For example, new imaging technolo-gies have the potential to track where drugs go inthe body, or visualize a drug’s immediate effects onabnormal collections of cells and on normal tissues.These uses of such functional imaging approachesare likely to be as common in the future as the useof the CT scan is now.

The convergence of these advances presents uswith the opportunity for a real revolution: to placethe discovery and development of drugs for cancerprevention and treatment on a firm scientific foot-ing. There is good reason to think that doing somay, within the next decade, lead to a whole newgeneration of cancer treatments and preventives.Yet, to ensure our success, we need to create con-ceptual and functional links among drug discovery,development, and clinical testing in ways that arecompletely unprecedented.

To understand why, consider the main ques-tions that researchers need to pursue about a newdrug’s effect on malignant or precancerous cells.Does the drug kill the cancer, or at least effectivelyblock its growth and spread? What part of thecell’s complex machinery does it disrupt and howis this disruption related to its anti-cancer effect?Until now, with our incomplete knowledge of can-cer, we had neither the knowledge nor the tools toaddress this second question, and thus, our clinicaltesting focused only on the first.

It is crucial that we gather the knowledge anddevelop the tools to answer both of these ques-tions. When we can, we will finally be able toaddress some of the most important questions incancer therapeutics. If a drug is working well, whyis it working, and if not, why not? Are we giving aperson the right amount, or too much, or too lit-tle? Do we have to give people the maximumamount of a drug that they can tolerate, or can wejudge the right amount by whether the drug is get-ting to the tumor and affecting its target? Will thedrug harm the patient, now or in the future? Onlywhen we can answer these questions will we be



Opportunities

able to predict who is likely to respond to a particular treatment and who will not. Moreover,information from the clinic and from the laborato-ry will reinforce each other, providing the basis forthe design of even better drugs in the future.

Timely investment in this area is critical. If theNCI does not invest now, engaging academically-based cancer biologists will depend on the align-ment of their discoveries with the product devel-opment goals of individual companies. Thisprocess will be incomplete and will not necessarilyemphasize the compounds, hypotheses, orapproaches that are likely to yield the most far-reaching advances. Because most companies’efforts are highly focused, many important scien-tific opportunities will not be explored in a timelymanner. Most importantly, development of thepractical tools needed to enable assessment of adrug’s effects on its molecular target in vivo willnot happen quickly or systematically, and informa-tion and reagents will not be made publicly avail-able as soon as they might have been.

THE GOALS

■ Transform the process by which cancer thera-peutics and preventives are discovered, devel-oped, and tested in the clinic.

■ Base discovery and development on interfer-ence with specific molecular targets in prema-lignant and malignant cells and in the tissuessurrounding the malignancy that sustain itsgrowth and spread.

■ Expand the involvement of the entire cancerresearch community in the discovery and devel-opment process.

THE PLAN

Objectives1. Identify and characterize molecular targets

for drug discovery. ■ Fund Molecular Target Discovery Grants to

provide researchers working on cancer mech-anisms with the resources to develop the evi-dence that a new cancer-relevant molecule orpathway is, in fact, a promising target for drugdiscovery. Such evidence will establish the

credentials of a molecule or pathway as a suit-able target for prevention or treatment dis-covery efforts.

■ Supplement existing grants to support thesynthesis of target molecules in sufficientquantities necessary to characterize them biologically and determine their physicalstructure.

■ Supplement existing grants for structuralstudies involving collaborations between cancer biologists and structural biologists todetermine the physical structure of targetmolecules through x-ray crystallography ornuclear magnetic resonance.

■ Convene a panel of experts to assist NCI inprioritizing the targets emanating from thisprogram, to pinpoint those worthy of furtherresearch and development.

2. Develop assays (tests) for molecular targets.■ Contract with organizations expert in state-

of-the-art drug screening technology to devel-op sensitive, high throughput assays for prior-ity molecular targets to assess the effects ofcompounds on a target. The result of thiseffort will be a practical screen for every highpriority target, through which thousands ofcompounds can be tested daily.

3. Establish chemical and biochemical diversity libraries.■ Assemble and curate a “Library of Libraries” –

a rich collection of small molecule chemicallibraries derived from combinatorial synthesisprograms. The library, assembled in collabora-tion with chemists from academia and indus-try, will complement NCI’s existing reposito-ries of natural product extracts and syntheticchemicals. These libraries will be formattedto be suitable for screening and will be widelyavailable to researchers.

4. Foster interactions between assay developersand diversity libraries. ■ Make diversity libraries widely available to

researchers with assays. Create a sophisticatedinformatics system annotating the chemicalrepositories to ensure researchers’ access tolibraries most appropriate for their scientificorientation. NCI staff and outside expertswill work together to match biologists withinnovative assays to chemists having librariesof potential relevance to those assays.

■ Double the number of Chemistry-BiologyCenters in which chemists and biologists create highly integrated programs that com-bine chemical diversity generation with theuse of these compounds in “smart” highthroughput screens.

5. Screen compound libraries. ■ Fund contracts for drug screening to identify

chemicals or biologics that hit our prioritytargets. Use the assays developed with oursupport to screen compound libraries fromour collections. The most promising com-pounds identified from this process willundergo chemical optimization, and the bestoptimized compounds will be developed intodrugs suitable for clinical testing.

6. Create the tools and methods to make possibletarget-based clinical testing.■ Establish Centers of Excellence for Drug

Development organized around a mechanismof particular relevance to cancer preventionor therapy, such as angiogenesis, cell-cyclecontrol, immunotherapy, DNA-damagerepair, cell signaling, differentiation, metastasis, or apoptosis. These multidiscipli-nary research groups of chemists, biologists,pharmacologists, imagers, clinicians, andinformatics experts will create the tools necessary to clinically assess and validate theeffects of drugs on molecular targets. Allreagents developed in these centers will bemade available to the research community.

■ Provide supplements to Centers of Excellencefor Drug Development. Supplements willenable a Center to work with other investiga-tors and NCI to develop specific compounds.Companies will be able to provide resourcesto the Centers for similar collaborations.

■ Increase support to the National CooperativeDrug Discovery Group program. This NCI-funded program supports consortia of academ-ic institutions and pharmaceutical companiesdiscovering and developing targeted drugs.

7. Expedite the steps that turn a chemical or a biologic into a drug suitable for initialclinical testing. ■ Fund contracts for drug-lead optimization and

drug development. Contracts with chemists

in academia and industry will support opti-mizing lead structures produced by target-based discovery activities that result in candi-date compounds for clinical testing. NCI’scontracts program for pharmacology, synthe-sis, formulation, and toxicology will supportthe advancement of these drug candidates tothe clinic. Fast-response contracts will assistin developing assays for particular agents inNCI’s development pipeline.

■ Support optimization of target-directed bio-molecules. NCI will increase support for opti-mization of the interaction of biomolecules(for example, monoclonal antibodies) withtheir targets by exploring the effects ofsequence diversity on important propertieslike target affinities and selectivity.

■ Competitively fund Rapid Access toIntervention Development (RAID andRAPID) contracts for academic drug discov-ery laboratory needs. The contracts will sup-port novel discoveries through the develop-ment steps necessary to take a new discoveryinto the clinic for proof-of-principle testing asa potential therapeutic or preventive.

8. Expand Resources and infrastructure.■ Create standards and expedite access to bio-

logical resources. The availability of standard-ized reagents (cell lines, growth factors) orassay conditions is critical to further progress.In collaboration with the investigator com-munity and with industry, NCI will createstandards for assays and reagents. If access is asignificant research barrier, NCI will create adistribution system to expedite access to cru-cial reagents at reasonable cost.

■ Fund synthesis of chemicals and biologicalsand provide them to the research community,on a competitive basis, to advance the drugdiscovery effort and move promising com-pounds to clinical trials.

■ Develop data bases of drug screening resultsand create a publicly accessible Web site thatadvertises the availability of chemical andbiological resources and expedites interac-tions between research groups.



Opportunities

Identify and characterize molecular targets for drug discovery. $7.5 M■ Fund Molecular Target Discovery Grants (R01, R21/R33, SBIR/STTR).■ Fund up to 5 grant supplements to support the synthesis of target molecules.■ Fund up to 5 grant supplements to determine the physical structure of target molecules.■ Convene a panel of experts to assist in prioritizing targets.

Develop assays for priority molecular targets. $0.5 M■ Develop sensitive, high throughput assays.

Establish chemical and biochemical diversity libraries. $2.0 M■ Assemble and curate a collection of small molecule chemical libraries derived from combinatorial

synthesis programs.

Foster interactions between assay developers and diversity libraries. $6.5 M■ Make diversity libraries widely available to researchers with assays. ■ Double the number of Chemistry-Biology Centers (U19).

Screen compound libraries. $0.6 M■ Fund drug screening contracts to identify chemicals or biologics that hit priority targets.

Create tools and methods for target-based clinical testing. $22.5 M■ Establish 10 Centers of Excellence for Drug Development (P50).■ Supplement P50 grants for Centers of Excellence for Drug Development to support collaborations.■ Increase support to the National Cooperative Drug Discovery Group program.

Expedite steps that turn a chemical or biologic into a drug suitable for initial clinical testing. $20.5 M■ Fund contracts for lead optimization and drug development.■ Support optimization of the interaction of biomolecules with their targets.■ Fund RAID and RAPID contracts for drug development needs of academic discovery laboratories.

Expand resources and infrastructure. $4.3 M■ Create standards and distribution system for biological resources. ■ Synthesize and provide chemicals and biologicals to research community.■ Develop data bases of drug screening results; create publicly accessible chemical and

biological resources Web site.


TOTAL $66.4 M

Resources: Molecular Targets of Prevention and Treatment

THE OPPORTUNITY

The numbers are truly alarming. Every day,across this country, more than 3,000 youths

will begin to smoke, placing themselves atincreased risk for a host of cancers – lung, mouth,pharynx, larynx, esophagus, pancreas, cervix, kid-ney, and bladder – as well as heart disease and arange of other conditions. Of those who continueto smoke, approximately one half will die prema-turely, losing an average of 20 to 25 years of theirlife expectancy. And an estimated 450,000 peoplein the U.S. will die this year alone from tobacco-related diseases – the most preventable and costlycause of death in our Nation. The global picture iseven more sobering: More than one billion peoplesmoke worldwide and an estimated three milliondie annually from tobacco-related illness.By 2025, the number of deaths is expect-ed to reach ten million per year.

These statistics illustrate dramaticallythat tobacco – through the use of ciga-rettes, cigars, pipes, and smokeless prod-ucts – poses an extremely serious threat topeople’s health worldwide. They alsounderscore the urgency of addressing thisthreat. Evidence demonstrates stronglythat people who stop smoking – regardlessof age – live longer than those who continue tosmoke, although their risk for lung cancer remainssomewhat higher than if they never had smoked.To respond to this major threat to life and health,NCI has established decreasing tobacco use as anarea of extraordinary opportunity.

Seizing this opportunity, however, presents asignificant challenge to NCI and to the researchand public health communities. In a field whereevery need seems pressing, we must identify whereresearch is most needed and how best to prioritizeand achieve scientific objectives with the greatestbenefit. As a first step, NCI established theTobacco Research Implementation Group

(TRIG), bringing together two dozen leading sci-entists and experts to identify tobacco-relatedresearch priorities for the next five to seven years.The TRIG identified and prioritized a set of nineoverarching research opportunities. Pursuing thesepriorities promises to alter dramatically the waytobacco research is conducted on a national scaleand to speed the pace of discovery to help reversetoday’s epidemic of tobacco use and tobacco-relat-ed cancers.

Developing Optimal Prevention andCessation StrategiesStudies indicate that the majority of smokers wantto stop smoking completely but struggle to quit.And most adolescents who smoke regret everstarting. Thus, developing strategies that prevent

people from ever starting to smoke andhelp those who currently smoke to stop is a critical need.

In the last three decades, we have wit-nessed many achievements in this area ofresearch: the development and implemen-tation of physician training and office pro-tocols for smoking cessation programs; theconfirmation of the effectiveness of pri-mary care medical and pharmacologicinterventions; the development of effec-

tive self-help interventions; and the developmentof new tailored, proactive interventions designedto meet the needs of individual smokers. In addi-tion, mass media interventions capable of reachinglarge numbers of people with prevention and ces-sation messages have been developed and strate-gies aimed at reaching minority, ethnic, and high-risk populations have been tested. Recent largeprograms, like the Community Intervention Trialfor Smoking Cessation (COMMIT) and theAmerican Stop Smoking Intervention Study(ASSIST), have shown both the potential and thelimitations of community and state tobacco con-trol interventions for changing attitudes about

Research on Tobacco and Tobacco-Related Cancers 5 O P P O R T U N I T Y


For more

information on

TRIG, visit

http://dccps.

nci.nih.gov/

tcrb/TRIP/

http://dccps.nci.nih.gov/tcrb/TRIP/

tobacco use, changing tobacco use behaviors, andreducing the tobacco-related cancer burden. Yetwe still do not fully understand the most criticalelements of tobacco prevention and treatmentstrategies, their timing, how best to target high-risk subgroups and settings, and how to tailor mes-sages and materials appropriately for different pop-ulations.

Identifying and Targeting Populations atHigh Risk for Tobacco-Related Cancersand Nicotine AddictionWe have made enormous progress in understand-ing the molecular and genetic factors that underliethe transformation of a normal cell to a cancercell following exposure to tobacco carcinogens.For example, scientists have identified many can-cer-causing agents contained in tobacco smokeand shown that different tobacco products andmethods of nicotine delivery influence the typeand quantity of exposure to these agents.

Researchers also have determined that thesemultiple agents seemingly induce similar changesin a cell, regardless of the cell’s location in thebody. The challenge now is to learn more about

how and why elements in tobacco smoke targetparticular genes and how tobacco-induced cellulardamage initiates and promotes cancer’s develop-ment. Such knowledge, gained through studiesusing preclinical models, will help us identify pre-cancerous lesions and markers that may predicttobacco-induced cancer. Identifying markers thatdetect DNA damage and other antecedents of can-cer will enable us to test different prevention andtreatment strategies and develop new early detec-tion methods. It also will enable us to determinethe amount of carcinogens in different tobaccodelivery systems, the effects of burning tempera-tures on tobacco additives, and how tobacco smokecomponents interact with each other.

This research also could provide importantinsights into why some people may be particularlyvulnerable to harm from tobacco. For example,women develop more lung cancers than men percigarette smoked. Certain ethnic groups appear tobe at increased risk for lung cancer as well. Whilethe reasons for these differences are not clear,smokers with certain gene variants are more likelyto be lung cancer victims. Therefore, we need todevelop preclinical models that will enable us toidentify the harmful variants that lead to increasedsusceptibility to tobacco-related cancers to helpdetermine why some individuals exposed to tobac-co are particularly susceptible to cancer, whileothers are spared. Using this information andknowledge of how inherited susceptibilities andtobacco exposure contribute to cancer in combi-nation, we can develop specific prevention anddetection strategies and target them to vulnerableindividuals.

Further, there is increasing evidence that genesinteract with environmental factors to influencewhether an individual will start smoking, howearly he or she will start, and how difficult it willbe for him or her to quit. Just as we now knowmore about the biological bases of tobacco-relatedcancers, we also have learned a great deal aboutthe psychosocial, biobehavioral, and biologicaldeterminants of tobacco use and addiction. Weknow, for example, that adolescent tobacco use istied to peer and family influences and low self-esteem. We also know that continued smoking byadults is associated with nicotine addiction,depression, and stress. More recently, majorresearch breakthroughs have provided important


Opportunities

About Tobacco■ Tobacco is responsible for more than 30 percent

of all cancers and nearly one in five deaths in the U.S. every year.

■ In the last decade, more than four million people inthis country lost their lives to tobacco-related diseases,including, according to Environmental ProtectionAgency estimates, more than 30,000 nonsmokers who died of lung cancer caused by breathing smokefrom others’ cigarettes.

■ The number of tobacco-related deaths in the U.S. continues to rise, particularly among women.

■ The financial costs of tobacco also are rising. Over the course of their lives, current and former smokersgenerate an estimated $501 billion in excess healthcare costs. Tobacco costs Medicare a staggering $10 billion each year and Medicaid more than $12.9 billion annually.

■ Smoking among U.S. adolescents has increased by 73 percent in the last 10 years, and the declines inadult smoking appear to have leveled off.

■ Rates of smoking are disproportionately high amongcertain population groups, such as African Americans.


My father was just diagnosed withlung cancer. He quit smoking twen-ty years ago — we never dreamedhe would still be at risk.

Cigarette smoking is by far the singlegreatest risk factor for lung cancer,which will cause nearly 160,000deaths this year. Current smokers areat highest risk, but lung cancer doesoccur in former smokers even yearsafter they have quit. Research isurgently needed to determine how todecrease the risk of tobacco-relatedcancers in former smokers, who nownumber nearly 50 million. Researchalso is needed to find these cancerswhen they are small and curable. Lungcancers can occur in people who havenever used tobacco. Other factorsshown to increase lung cancer riskinclude recurrent lung inflammation,air pollution, exposure to radon gas

(especially in combination with tobac-co smoke), and exposure to asbestosand other industrial carcinogens.

We found out about a clinical trial ofa new treatment for people with thekind of lung cancer my father has –the early results look promising.

Treatment for both major types oflung cancer – small cell and non-small cell – remains extremely diffi-cult, but we are achieving modestincremental improvements. Advancesin combination chemotherapy andradiation regimens have played themost significant role in treating smallcell lung cancers, while refined surgi-cal techniques have been most impor-tant in improving the outlook forsome patients with early non-smallcell lung cancer. Other advances maybe on the horizon. Early study results

suggest thatphotodynamictherapy – theuse of lasers andlight-activateddrugs to killtumors – mayhold promise forcertain groups ofpatients withearly lung can-cers and forsome patientswho cannotwithstand sur-gery. In anotherearly clinicaltrial, administra-tion of a geneti-cally altered

virus successfully replaced faulty p53 tumor suppressor genes inpatients with advanced lung cancer,leading to disease stabilization ortumor shrinkage for some patients,and in one case, complete remissionof disease. Though more research isneeded to demonstrate their benefit,approaches such as these may eventu-ally offer lung cancer patients newtreatment options.

I smoke. I know it sends the wrongmessage to my daughter.

Each day, 3,000 American youthbecome smokers. If they continue tosmoke, as many as half will eventuallydie a premature, tobacco-relateddeath – many of these deaths willresult from lung and other smoking-related cancers. Cigarette smoking isagain increasing among teenagers,and recent evidence indicates thatsmoking rates also are rising markedlyamong college students. New studiesshow that people who begin smokingas adolescents are more susceptibleto long-term DNA damage associatedwith lung cancer. Smoking amongwomen continues to escalate, as doestheir lung cancer incidence and mor-tality, which exceeds that of breastcancer. Moreover, cigar smoking,which increases risks of lung and oral cancers, is increasing among bothwomen and men. Recently, a gene hasbeen discovered that appears toaffect how easily a person becomesaddicted to nicotine.

P e o p l e ’ s S t o r y

Lung Cancer


Opportunities

Especially now, since my father’sdiagnosis, I want to try to quitsmoking. I’ve failed so many timesbefore, but I think this time will bedifferent.

Nearly a quarter of the U.S. adultpopulation smokes, but most smokerswant to quit. Furthermore, nearly onethird of all cigarette smokers attemptto quit each year, but only a smallpercentage actually succeed. Newsmoking cessation aids have becomeavailable in recent years to helpsmokers – nicotine gum, the nicotineskin patch, the antidepressant drugbupropion, and smokeless nicotineinhalers. A recent study found thatafter one year, almost 36 percent ofthose using the patch and bupropiontogether remained abstinent, com-pared to those using bupropion alone(30 percent) or the patch alone (justover 16 percent). Evidence also indi-cates that quitters using a cessationaid who also get counseling fromtheir health care provider have bettersuccess than those who do not.

Following the recommendations of itsTobacco Research ImplementationGroup (TRIG), NCI, in collaborationwith the National Institute on DrugAbuse, will soon launch a network ofTransdisciplinary Tobacco ResearchCenters to study tobacco use initia-tion and prevention, tobacco addic-tion and its treatment, and the treat-ment of tobacco-related cancers. TheTRIG also has recommended targetedresearch initiatives to identify cultur-al, psychological, and genetic factorsthat influence smoking behavior inchildren and adults. Other initiativeswill focus on improving the dissemi-nation of proven prevention and

treatment interventions at the stateand community levels, and on tailor-ing tobacco control programs for populations at high risk.

I’ve learned that even if I neversmoke again, my lung cancer riskmay always be higher than someonewho never smoked. My doctor told mesome signs of trouble to watch for.

Though most lung cancers cause nosymptoms until they are advanced,smokers and former smokers should beespecially alert for symptoms that maysignal early lung cancer. These includea persistent cough, hoarseness, chestpain, loss of appetite and weight loss,bloody or rust-colored sputum, short-ness of breath, fever without apparentreason, recurring bronchitis or pneu-monia, and wheezing. Any of thesesymptoms can be caused by other dis-eases, but seeing a doctor promptly isthe only way to find out if they arebeing caused by a lung cancer.

Watching for such signs is especiallyimportant since no reliable procedurefor routine lung cancer screening isyet available. Encouraging resultsfrom an early trial of spiral computedtomography (spiral CT) for lung can-cer detection suggest that furtherdeveloping this technology may leadto an affordable, accurate lung cancerscreening test in the coming years.

Research also is being conducted tolearn more about former smokers’long-term risk for lung and other can-cers. In addition, for those lung can-cers not attributable to tobacco use,NCI is continuing research to learnmore about how genes, the environ-ment, and other factors may con-tribute to lung cancer developmentand progression.

This vignette is a composite of experiences.

Annual Percent Change in Mortality Lung & Bronchus Cancers 1990-1996All Races

Significant Yearly Increase

No Changes

Significant Yearly Decrease

FEMALESMALES

insights into the biological bases of tobacco useand nicotine addiction, including the role ofgenetic factors and ethnicity in nicotine metabo-lism. For example, researchers have identifiedgenes that modify nicotine metabolism and regu-late brain chemicals that affect the pleasurablefeelings triggered by nicotine. These discoveriesprovide unique opportunities for studying the linksbetween biology and behavior and will help iden-tify preexisting vulnerabilities to tobacco use. Bydetermining how these vulnerabilities interactwith sociocultural and psychological influences ontobacco use, and by improving our ability to assessrisks quantitatively, we can develop more effectiveprevention and cessation interventions and tailorthese interventions to the people most likely tobenefit from them. We also can identify effectivenew drugs and combinations of already provendrugs for treating nicotine addiction. The combi-nation of pharmacologic and behavioral tailoringmay be particularly important in acceleratingmajor improvements in smoking cessation rates.

Capitalizing on Social, Legal, and Public Policy DevelopmentsA number of social, legal, and public policy devel-opments are converging with scientific advancesto create a unique opportunity to tackle tobaccouse. Public attitudes reflect decreasing acceptanceof tobacco use as a social norm. For example, con-cerns have been raised about the targeted market-ing of menthol cigarettes in the African Americancommunity. Government agencies, academic insti-tutions, and professional and voluntary organiza-tions are making major commitments to reducetobacco use and exposure to tobacco carcinogens.Through lawsuits, states are recovering billions ofdollars lost to the treatment of diseases caused bysmoking. However, while state political leadershave been urged to use these funds to expandtobacco control programs, they almost certainlywill use most of the funds to address other priori-ties. This dilemma underscores the need for NCIto expand its investment in tobacco controlresearch to ensure that the best scientific evidenceinforms state and community programs. How canwe help policy makers develop effective programswhen we do not know the full impact on tobaccouse of clean indoor air policies, marketing restric-tions, and youth access restrictions, all of which

are pillars of tobacco control but face stiff andsometimes passionate resistance?

In summary, we have an unprecedented oppor-tunity to reduce the enormous burden of tobaccouse on our Nation’s public health. The investmentproposed here will enable us to gather knowledgethat will inform policy makers and public healthpractitioners about the best strategies for preven-tion and treatment; this is of special concernbecause states must decide how best to use tobaccocompany settlement funds for tobacco controlefforts. Our collaborations with Federal and stateofficials will help ensure that these funds are spentin ways that will maximize tobacco control bene-fits and save lives.

More effective smoking cessation programsalone could save many of the nearly 160,000 liveslost to lung cancer each year. An expanded tobac-co control research program covering biologicaland biobehavioral research; clinical, epidemiolog-ic, surveillance, and policy research; and supportfor research infrastructure, will be essential toachieving our goals.

THE GOALS

■ Define the biological, behavioral, and societalbases of tobacco use and addiction.

■ Reduce tobacco use rates among youth andadults, and especially among high-risk groupsincluding low income, minority, and medicallyunderserved smokers.

■ Define the relationship between exposure totobacco products and carcinogenesis.

■ Prevent cancer in former smokers.

THE PLAN

Objectives1. Develop more effective interventions to

prevent tobacco use.■ Initiate trans-NIH efforts to determine the

interdependent causes of tobacco use, espe-cially among youth. These efforts shouldinclude epidemiological studies, such as lon-gitudinal cohort designs, to track familial,environmental, and biological risk factorswithin the same individuals over time,



Opportunities

enabling us to better understand the determi-nants and health consequences of tobacco usein children and adults.

■ Fund a consortium of prevention scientists todevelop targeted tobacco use preventionstrategies for high-risk populations.

■ Establish a tobacco policy research consor-tium to determine the impact of pricing poli-cies, clean air policies, marketing and accessrestrictions, and tobacco product and nico-tine replacement regulation on tobacco use.

2. Develop more effective strategies for tobaccocessation, including those tailored for high-risk individuals.■ Develop more powerful pharmacotherapies by

discovering new drugs, combining provendrugs to determine additive effects, andstudying long-term use to improve cessationmaintenance.

■ Develop new behavioral techniques and tech-nologies that will amplify the effects of othertreatments; tailor therapies to smoker charac-teristics such as age, race and ethnicity, cul-ture, income, education level, psychiatric co-factors, other diseases, and even geneticmakeup.

■ Conduct controlled intervention trials toidentify optimal ways to disseminate andimplement proven tobacco-use preventionand treatment strategies.

3. Expand initiatives exploring genetic/environ-mental interactions that influence smokingbehavior and increased risk for cancer.■ Support research to identify genes related to

addiction.■ Fund studies to understand how environmen-

tal and other factors interact with genes toinfluence the likelihood and age of smokinginitiation, intractability of addiction, and riskof tobacco-related disease, such as lung cancer.

■ Encourage collaborations with internationalinvestigators to enable us to pursue uniqueresearch opportunities involving resourcesnot available in the U.S.

4. Develop approaches to prevent cancer in former smokers.■ Expand NCI’s Early Detection Research

Network to identify and validate markers oftobacco exposure and tobacco-induced cellu-lar events leading to carcinogenesis.

■ Support preclinical model development andsmall clinical trials to test preventive agentsor cancer therapies for people with a historyof tobacco exposure and the highest risk ofdeveloping cancer.

■ Fund innovative studies to determine themechanisms by which tobacco use con-tributes to the development of non-aerodiges-tive cancers such as pancreas, cervix, andbladder cancers.

5. Expand the national research infrastructure tosupport tobacco use research across disci-plines, provide training to new investigators,and monitor trends in tobacco use and tobac-co-related cancers.■ Expand support for transdisciplinary tobacco

use research and training. – Use the Transdisciplinary Tobacco Use

Research Centers (TTURCs) to bringtogether and foster collaboration amongtransdisciplinary teams of scientists.Establish new TTURCs to expand thescope of research conducted at existingTTURCs.

– Support transdisciplinary research throughother mechanisms and increase support fortraining in tobacco research, especiallyamong minority investigators.

– Establish a clinical research program atNCI where scientists from NIH and theextramural community can collaborate andrapidly implement cutting-edge research onnicotine addiction and tobacco use.

■ Expand surveillance systems to monitortobacco use behaviors, the implementationand durability of tobacco-related interven-tions, and other factors that influence tobacco use.


Resources: Research on Tobacco and Tobacco-Related CancersExpand research on tobacco use prevention. $11.0 M■ Initiate trans-NIH effort to determine interdependent causes of tobacco use.■ Fund a consortium to develop targeted prevention strategies for high-risk populations.■ Establish a tobacco policy research consortium.

Develop improved tobacco-use treatment strategies. $12.0 M■ Develop and evaluate new drug and drug combination treatments for tobacco addiction.■ Develop tailored behavioral techniques, technologies, and treatments.■ Conduct controlled intervention trials.

Conduct genetic epidemiology research. $6.0 M■ Supplement research grants to accelerate the discovery of nicotine addiction-related genes. ■ Establish cohorts to study the etiology of tobacco use.■ Initiate international collaborative studies to identify genes-environment interactions influencing

tobacco use initiation, cessation, and cancer development.

Prevent cancer in former smokers. $4.0 M■ Expand Early Detection Research Network to identify and validate markers of tobacco

exposure and carcinogenesis.■ Support pilot projects to develop and test preventive agents or therapies.

Conduct basic biological research. $7.0 M■ Initiate prospective studies to identify genetic and biological factors affecting vulnerability to

tobacco-related cancers.■ Fund innovative studies to determine how tobacco use contributes to non-aerodigestive cancers.■ Develop and use a Tobacco Carcinogenesis Models forum to link Mouse Models of Human Cancer

Consortium participants to investigators with expertise in behavioral and other models of tobaccocarcinogenesis.

Expand surveillance. $3.0 M■ Expand surveillance systems to monitor tobacco use behaviors, tobacco-related intervention,

implementation and durability, and other factors.

Enhance national research infrastructure. $20.0 M■ Double the number of TTURCs to expand the scope of research and capitalize on new discoveries. ■ Fund transdisciplinary research and training programs.■ Create a NCI clinical research program on nicotine addiction and tobacco use.


TOTAL $66.0 M


Opportunities

Cancer Communications 6O P P O R T U N I T Y

THE OPPORTUNITY

We are in the midst of a communications revo-lution unparalleled since Gutenberg intro-

duced movable type to the western world in the15th century. At no other time in history has itbeen so easy for so many people to access such avast wealth of information. In particular, theInternet has multiplied exponentially our abilityto make large amounts of information available toa wide audience quickly and easily.

Communication is central to effective, qualitycancer care, from primary prevention to survivor-ship and end of life issues. Communicationempowers people; it can raise awareness of healthproblems and recommended actions, and give peo-ple the information they need to make informedcancer-related decisions. Effective communica-tions can move people to engage in behaviors thatwill improve their health, such as stopping smok-ing or undergoing screening for certain types ofcancer. The Department of Health and HumanServices’ Science Panel on InteractiveCommunications and Health has concluded thatfew other health-related interventions have thepotential of interactive health communications to simultaneously improve health outcomes,decrease health care costs, and enhance consumersatisfaction.

Scientists and communications experts havebeen studying the process of effective communica-tion and its impact on health for more than 25years. They have produced increasingly refinedtheories of health communication, including thosethat focus on how people process health informa-tion and how they respond to cancer-related risks.These theories have enabled us to refine messagesfor people who differ in their readiness to takeresponsibility for their health. For example, inter-

vention research on effective health communica-tions has contributed to declining smoking ratesamong many groups in the U.S. Likewise, it hasinfluenced the increasing proportions ofAmericans who are eating five fruits and vegeta-bles per day, and getting screened for breast, cervi-cal, and other cancers.

Moreover, changes in the role and accessibilityof information are altering health care practices,patient-physician relationships, and the way con-sumers and patients acquire and use information.Where once physicians were the main source ofhealth information, now many consumers areactively seeking information to meet their needs.The commercial sector has responded to this para-digm shift by developing new communicationstechnologies at a dizzying rate. As we enter the21st century, consumers and professionals alikehave, or will have, a host of new opportunities forcreating, distributing, and acquiring health infor-mation from the World Wide Web, individually-tailored print and multimedia materials, interac-tive computer games, interactive kiosks, and wire-less pagers, among others.

It is impossible to overstate the impact of these“new media” on health communications.Consider, for example, the fact that: ■ In 1998, 22.3 million adults in the U.S.

searched on-line for health and medical infor-mation, and cancer was one of the most sought-after topics.

■ Also in 1998, 1.3 million pieces of e-mail wereprocessed each week by cancer-related listservs(e-mail groups devoted to a specific topic) hosted by the Association of Cancer On-lineResources.

■ In 1997, 41 percent of U.S. households had atleast one personal computer, and that numbercontinues to increase.

But this new world of expanded communica-tions capabilities remains in many ways unchartedterritory. Important questions confront us. Howcan we promote the demand for, access to, and useof cancer information, given the high nationalrates of medical illiteracy? How can we ensure thatcancer communications are salient, accurate, rele-vant, and culturally sensitive to diverse audiences?How can we better design our interventions to usewhat works, to know what does not work, and tounderstand why? How can we help physicians tomaximize their communication about cancer?How can we redesign information systems so theygive people the information they want, how theywant it, when and where they want it?

In addition, substantial barriers prevent majorsegments of the population from seeking and/orusing cancer information. Some people continue tolack access to the medium. Others are faced withcontent that is unintelligible (i.e., in the wronglanguage or in language that is too complex), cul-turally inappropriate, or simply ineffective.

Furthermore, despite our progress in refininghealth communications theories, major gapsremain in our understanding of how consumers usehealth information. We must learn how to helppeople distinguish important from insignificanthealth risks and deal with contradictory healthmessages so that they can make informed choices.We must provide accurate and balanced informa-tion about all areas of cancer treatment and care,including complementary and alternative thera-pies. We must find the best ways to inform doctorsof emerging “best practices” in patient care. Andwe must find ways to help physicians be moreeffective communicators and integrate cancercommunications into all aspects of cancer care.

Cancer communication must be used to narrowthe enormous gap between what we know andwhat we do at all levels and to reduce health dis-parities among our people. For example, newavenues are needed to reach children, especiallythose in vulnerable, high-risk populations. NCI iscommitted to improving demand for, access to,

and use of cancer information for all, regardless ofrace, ethnicity, health status, education, income,age, gender, or geographic region.

Finally, new information technologies mustcomplement, not replace, older but effective strate-gies, such as the mass media, one-to-one counsel-ing, and targeted print communications. We know,for example, that many people still want to talkwith a knowledgeable and supportive person. Aswe develop new technologies, we must not losesight of the importance of the human bond.

To be effective, cancer communications mustbe integrated into the cancer continuum – fromprevention through treatment to survivorship andto end of life issues, including palliative care andpain management. Communication should be anintegral component of quality cancer care. NCIand its grantees and contractors have traditionallybeen leaders in health communication, but it istime to go beyond what we have done before – totake advantage of new knowledge about healthbehavior and new technology – to reduce the bur-den of cancer. If NCI takes the lead now, we havethe opportunity to use both proven strategies andnew communications technologies to help peopleincrease their knowledge, enhance their ability tonegotiate the health care system, understand andmodify their health risk behaviors, speed the paceof discoveries, and increase access to and partici-pation in clinical trials. Moreover, we will have afar richer understanding of how people use com-munications technologies of all kinds. Ultimately,we will improve outcomes in cancer prevention,early detection, treatment, and survivorship.

By investing now, we will seize a crucial oppor-tunity to shape the emerging national informationinfrastructure to improve cancer communications.At this pivotal juncture, there is a need for a pub-lic institution such as NCI to provide leadershipin the cancer communications arena; the broadand reasoned perspective that NCI brings topatients and health care providers alike is essentialto successfully implement communications strate-gies to reduce the cancer burden.


THE GOALS

■ Accelerate reductions in the U.S. cancer bur-den through the use of cancer communications.

■ Integrate cancer communications into the can-cer continuum so that it is an accepted andpracticed component of quality care.

■ Increase the demand for, access to, and use ofcancer communications by diverse populationsincluding the public, high-risk persons, under-served and disabled populations, children,patients, survivors, and health professionals.

■ Use cancer communications to speed the dis-semination of “best practices” across the cancercontinuum from prevention through treatmentand survivorship or end of life.

■ Strengthen and monitor the use and efficacy ofNCI’s own communications and communica-tion products.

■ Develop the infrastructure needed to accelerateadvances in cancer communications, such asthe testing of strategies, models, and tools; anddissemination of results to researchers, clini-cians, patients, practitioners, advocacy groups,other partners, and the public, including emerg-ing on-line communities of interest.

THE PLAN

Objectives1. Establish new data collection and analysis

strategies to obtain data at regular intervalsfor cancer communications planning,research, evaluation, and marketing. ■ Sponsor a triennial survey of a nationally rep-

resentative sample of the U.S. populationthat is conducted on a recurring basis withinput from investigators in the field.

■ Add questionnaire items to the NationalHealth Interview Survey and the CDCBehavioral Risk Factor Surveillance Surveyto more effectively monitor national trendsrelated to cancer communications.

■ Track promising new product development,monitor software developers and hardwaremanufacturers as well as market researchfirms that monitor developers and manufac-turers and often are the first to spot newproduct uses.

■ As technology evolves, monitor emerginginformation needs and ensure that mecha-nisms are in place to conduct the appropriateresearch to address unmet and perhaps previ-ously unarticulated needs.


Opportunities

Fundamental Assumptions of CancerCommunications■ Proactive communication strategies are needed across

the cancer continuum to rapidly accelerate a reductionin the cancer burden and across the life span.

■ A successful strategy requires that we reach a broad cross-section of the U.S. population.

■ NCI’s cancer communications should be based on scientific evidence obtained through high qualityresearch and its products should be evaluated for efficacy, impact, and use by the target audiences.

■ Access includes removing cost barriers and improvingease of use, familiarity, cultural appropriateness, andappeal of the medium.

■ Comprehension is essential, and messages must be perceived as salient, appropriate, and relevant.

■ We must offer a flexible and adaptable menu of communication choices to reach the public, patients,underserved populations, survivors, and health providers in diverse settings.

■ The new media should complement more “traditional”media such as mass media, the telephone, and one-to-one interpersonal communications.

■ We must forge effective partnerships with other NIH Institutes, the Centers for Disease Control andPrevention, voluntary health organizations such as the American Cancer Society, and advocacy and self-help groups.

■ Partnerships with industry and academia are essential to identify and gain access to emerging communicationtechnologies. These partnerships should include computer, telecommunications, pharmaceutical, insurance, and new media companies.

2. Create Cancer Communications Centers ofExcellence to provide interdisciplinary unitsfor communications research. ■ Facilitate rapid advances in knowledge about

cancer communications.■ Develop new theories of health and cancer

communications that are appropriate tounderserved populations.

■ Develop strategies to improve the penetra-tion, efficacy, effectiveness, and disseminationof cancer communications.

■ Identify optimal formats for communicatingcancer risks.

3. Develop an integrated cancer knowledge management strategy, including an adaptedCancer Information Service (CIS) that offersa menu of communication choices designed tomeet and respond to people’s diverse informa-tion needs. ■ Integrate NCI’s information services.■ Infuse new media technologies into all NCI

information services.■ Disseminate best processes.■ Support and use new research methodologies

and approaches to respond to the swift paceof change inherent in the communicationsrevolution.

■ Create an extended enterprise knowledgebase at NCI that integrates linkages to appro-priate external resources.

■ Foster cooperative relationships with otherpublic health agencies, advocacy groups, sup-port organizations, and industry.

4. Develop new communication products toimprove cancer communications to diverseaudiences.■ Develop and update regularly practical toolk-

its for the public, patients and their care-givers, underserved populations, advocacygroups, health professionals, and cancer com-municators to improve the state of cancercommunications.

■ Fund research to develop practical decisionaids to improve patient-provider communica-tion and to help people make better cancer-related decisions.

■ Fund workshops and seminars to promote dis-semination and use of these practical toolsand to solicit information concerning currentlevels of use and barriers.

5. Identify, create, and nurture the newest andmost promising communication technologies. ■ Collaborate with academia and the private

sector to encourage the development or newuses of software and hardware to improvecancer communications.

6. Train the health communications scientists,researchers, and practitioners needed toachieve our scientific and health communica-tions objectives. ■ Encourage the development of interdiscipli-

nary training programs that, at a minimum,include people in health behavior, marketing,engineering, communications, public health,and medicine.

■ Fund existing health communicationsresearch laboratories to conduct training pro-grams and provide opportunities for researchprofessionals in growing areas, including riskcommunication.



Opportunities

Resources: Cancer Communications

Expand data collection. $5.0 M■ Sponsor a nationally representative triennial survey and make results publicly available. ■ Add questions to established surveys to monitor national trends in cancer communication.■ Track promising new product development.

Establish 6-8 Cancer Communication Centers of Excellence. $12.0 M

Develop an integrated cancer knowledge management strategy. $10.0 M■ Integrate new media technologies into NCI information services; link to external resources.■ Support new research methods/approaches and disseminate best processes.■ Integrate new information technologies for easier, more efficient, and less costly organization,

packaging, and communication of cancer information for users with diverse needs. ■ Foster relationships with public health agencies, advocacy groups, and industry.■ Expand communication choices available through CIS. ■ Integrate the restructure of PDQ and the CIS activities into NCI’s clinical research program.

Develop practical tools for cancer communications. $3.5 M■ Develop toolkits for media, public, patients, underserved populations, advocacy organizations,

health professionals, and cancer communicators to improve cancer communications.■ Support development of decision tools, appropriate for underserved populations.

Identify, create, and support promising communications technologies. $1.5 M■ Expand JOLT (Joining Organizations with Leading Technologies).■ Co-sponsor state-of-the-art meetings on emerging technologies.

Foster interdisciplinary training and educational programs. $6.0 M■ Develop interdisciplinary training programs to prepare needed personnel in cancer-related

consumer health informatics and cancer communications. ■ Fund existing health communications research laboratories to conduct short- or longer-format

training programs for research professionals.■ Develop a Master’s Program in health communications and media technology delivery.

Develop NCI infrastructure in cancer communications research. $4.0 M■ Recruit staff expert in health communications and media development, use, and research.■ Create an in-house laboratory for testing cancer communications. ■ Implement freestanding science bureau to improve reporting in cancer communications.


TOTAL $43.0 M


As we begin the 21st century, we are withoutdoubt in a position to make real improve-ments in human health and disease. We

made remarkable progress in the 20th century inour knowledge of cancer biology, dramaticallyexpanding our understanding of what is requiredto turn a normal cell into a cancer cell. Recentlydeveloped molecular-based technologies are pro-viding even greater insights into the stepsinvolved in the transformation of cells from normal to precancerous to cancerous, allowing usto detect and diagnose cancers much earlier.Other advances in technology, such as new andenhanced imaging tools and techniques, coupledwith new drugs, targeted therapeutic interven-tions, and new insights and discoveries into thefundamental nature and causes of cancer, presentunprecedented opportunities for advancing ourunderstanding of cancer and improving quality of life for people diagnosed with cancer.

The challenge before us is to establish themechanisms that will allow the scientific commu-nity to apply these discoveries and emerging technologies to the field of cancer research. Weneed mechanisms that will promote and rewardinnovative thinking, the cross-fertilization of ideas among disparate scientific disciplines, andenhanced collaborations among government, academia, and industry. We also must develop and maintain the cadre of trained scientists from many disciplines needed to undertake thisessential work.

NCI’s role is to provide the vision, creativeenvironments, and diverse resources needed toensure a smooth flow between the increasing num-

ber of discoveries and advances in cancer researchand the scientific community’s ability to applythese findings to prevent and treat the many formsof cancer. Yet if the pace of discovery is like aneight-lane highway, our current ability to translatethose discoveries into clinical application is like acountry road. Where the two meet, a bottleneckof good ideas occurs. Our challenge is to expandthe country road to an eight-lane highway thatmoves discoveries swiftly to their use in interven-tions across the continuum of cancer care.

To respond to this challenge, we have identifiedsix key areas for investment – Investigator-Initiated Research; Centers, Networks, andConsortia; National Clinical Trials Program;Informatics and Information Flow; StudyingEmerging Trends in Cancer; and Training,Education, and Career Development. Each ofthese investment areas will play a unique role inour fight against cancer.

NCI’s Challenge: Building the Capacity of the Future

Challenge Program Increase(dollars in thousands)

Amount

Investigator-Initiated Research $ 146,015Centers, Networks, and Consortia 62,350National Clinical Trials Program 201,335Informatics and Information Flow 70,000Studying Emerging Trends in Cancer 56,600Training, Education, and Career Development 60,700

Total $597,000

NCI’s Challenge 75

Challenges

Investigator-Initiated Research 1C H A L L E N G E

THE CHALLENGE

Investigator-initiated research – research pro-posed and conducted by scientists in laborato-

ries and clinics across the country and here at NCI– is the wellspring of scientific discovery. Fundedand sustained by a variety of NCI grant mecha-nisms, our investigator-initiated research is contin-ually yielding discoveries and insights into themechanisms and causes of cancer and its preven-tion, detection, diagnosis, treatment, control, andsurvival. These discoveries, and their applicationin interventions of all kinds, are critical to reduc-ing the burden of cancer and are resulting in realprogress against cancer.

Through the dedicated work of these NCI-sup-ported scientists over the past 50 years, we standat the threshold of understanding a great unknown– how cancer develops at the molecular level.Because of our continued national commitment tocancer research, we are poised to expose more rap-idly than ever before the inner workings of cancercells, their genes, and the ways in which theybehave. We must push forward as quickly as possi-ble with this work. The absolute number and paceof our discoveries, and the speed with which webring them to bear to benefit people, are directlylinked to the level of resources available to sup-port the exploration of new leads across the cancerresearch continuum. Moreover, we must strive toexpand our research portfolio to include a greaternumber of research proposals that may be some-what riskier, highly speculative, or pursue novelpaths. We also must continue to expand the trans-lational research that converts basic science dis-

coveries into practical, affordable, and effectiveways of restoring cancer patients to health andpreventing cancer throughout our population.

As we promote innovative research, we mustcreate mechanisms that link basic, clinical, andpopulation-based research with state-of-the-artresources and technologies; promote collabora-tions among researchers inside and outside of can-cer research; and draw into cancer-related researchscientists from allied fields such as chemistry, biol-ogy, physics, and mathematics. By bringing togeth-er researchers from allied fields, we will galvanizethe complementary knowledge these individualspossess to most quickly answer the crucial ques-tions in basic, clinical, population, and transla-tional research. It is under this broad scientificumbrella that discoveries in the 21st century will be made.

The Nation waits eagerly for the day when can-cer is no longer a threat to health and life, whenmost cancers are prevented, and when those thatoccur are cured or controlled rapidly and success-fully. To meet this challenge, we must fuel thedrive to discover the unknown by increasing oursupport of innovative research and providing thesupport needed to exploit the discoveries it yields.Our research base should bring to bear the best ofour developing knowledge, as well as the best ideasand technologies, to address the full spectrum ofcancer research questions – from basic research toprevention and care. Continued investment in thiscrucial aspect of the research infrastructure willspan the gap between discovery and applicationand transform the processes by which we bring dis-coveries to the benefit of people.


THE GOALS

■ Increase the rate of discovery.■ Increase investigators’ access to state-of-the-art

resources, technologies, and infrastructures thatpromote collaboration and speed the pace ofdiscovery.

■ Accelerate the application of discoveries tobenefit people.

THE PLAN

Objectives1. Increase investment in research to ensure a

higher and sustainable success rate for com-peting grant applications. Today, NCI fundsjust over 30 percent of competing grant applica-tions through the Research Project Grant(RPG) pool. To ensure that a greater number ofexcellent ideas have the chance to be tested asquickly as possible, we need to:■ Fund 40 percent of competing applications,

including those that have the highest scien-tific merit, carry great risk but may yieldpotentially greater reward, are unconvention-al but hold unique promise, are in areas ofextraordinary need in specific fields of inves-tigation or model systems, or encourage newinvestigators.

2. Encourage investigators to commit to careersin cancer research and to propose more inno-vative and higher risk/higher reward projects. ■ Continue to allocate the first 80 to 90 per-

cent of available RPG funds to competingapplications that fall within conventionalmerit rank order paylines.

■ Assure that applications from new investiga-tors and applications that are particularlyinnovative and high risk/high reward have areasonable funding rate.

3. Enhance the opportunity for outstandingapplications that fall just beyond establishedpaylines to receive more rapid reconsideration. ■ Allocate up to 20 percent of available RPG

funds to award meritorious applications thatare outside conventional paylines, includingset-aside funds for Requests for Applications

(RFAs), Program Announcements (PAs), andapplications under other grant mechanisms.

■ Continue Accelerated Executive Review(AER) to fund single project applications inpatient-oriented and basic research that arenear the payline and for which reviewer criti-cisms can be addressed rapidly; apply a similarapproach to other application types, such asProgram Project Grants.

4. Invest in areas that NCI consensus planningprocesses (e.g., Progress Review Groups,Extraordinary Opportunity Working Groups,Advisory Committees) have identified as pre-senting special opportunity or need.■ Monitor investigator-initiated research appli-

cations to assess whether these projects aloneare meeting programmatic objectives.

■ Use as needed regular, novel, and specialaward mechanisms and incentives announcedthrough competitions (e.g., PAs, RFAs) toencourage investigation in particular areas.

■ Provide sufficient staff, resources, andenhanced electronic communications toimprove information dissemination, enhancecoordination within and between initiatives,and increase direct contact with applicantsand grantees.

5. Optimize each award to accelerate the pace ofdiscovery. In 1999, NCI grant awards averagedfour years in duration and were awarded 90 per-cent of recommended funds. This level of fund-ing and project duration slows discoverybecause fewer experiments can be conductedand fewer patients accrued to clinical trials. ■ Provide funding at full peer-reviewed

recommended budget levels for up to fiveyears of support.

■ Ensure that investigators have access to NCI-sponsored resources, infrastructure, and tech-nologies that facilitate discovery, both tomake progress as quickly as possible, and tocreate breakthrough opportunities.

■ Set aside funds to award as administrativesupplements to current awardees whoseresearch is going better than expected, orwho are poised to test new ideas.

■ Expand award mechanisms that provide seedfunds and resources to pilot promising leads.


Challenges

6. Facilitate rapid movement from discovery toapplication by encouraging interdisciplinaryand collaborative approaches.■ Use established mechanisms and create novel

and special mechanisms to encourage collab-orative and translational research. Broadenthe Phased Innovation Award to include anapplication phase.

■ Expand administrative supplements toencourage new collaborations that bringtogether basic and clinical scientists; promoteadditional interdisciplinary collaborationsand access to central resources such as databases, tissue banks, and animal models.

■ Foster and expand novel opportunities foraccess to resources and technologies that promote interdisciplinary research and collaborations through centers, networks, and consortia.

■ Expand cooperative resource programs thatgive investigators access to technologies andexpertise needed to move their discoveries toapplication.

■ Encourage the development of informationtechnology tools to facilitate interdisciplinarycommunication and collaboration.

■ Increase funding for collaborative researchawards such as Program Project Grants andcooperative agreement networks in cancergenetics, imaging, early detection, and other areas.

■ Expand use of exploratory grants to encour-age patient- and population-based research.

PROGRESS TOWARD MEETINGTHE CHALLENGE

Over the past four years, NCI has increased sub-stantially the number of investigator-initiated

grant applications funded. In 1995, the overallsuccess rate for grants funded from the RPG poolwas 23 percent. In 1999, we anticipate fundingmore than 1,200 new and competing grant appli-cations from the RPG pool, for an overall successrate of 33 percent. This increase has resulted inand will continue to yield many research rewards,but this improved funding level is still insufficientto support the wealth of innovative, high qualityproposals received each year. In fact, as we attractnew researchers to the cancer problem the numberof excellent, innovative applications can only beexpected to grow.

To encourage both the development of newtechnologies and innovative approaches to specificareas with special needs, NCI has implementedseveral new or expanded mechanisms. For exam-ple, the Quick-Trials program was designed tospeed the translation of ideas to early stage clinicaltrials. The Phased Innovation Award programsupports novel technology development for molec-ular analyses of cancer. Both programs promise toencourage innovative approaches and increase thespeed at which discoveries are translated to clini-cal application. Through a special exceptionsprocess, NCI ensures that new investigators sharethe same success rate as more established R01applicants. In addition, the Accelerated ExecutiveReview process ensures rapid reconsideration ofapplications ranked within a few percentile pointsof the payline, especially those involving patient-oriented research.


Resources: Investigator-Initiated Research

Ensure sustainable success rate for competing applications. ■ Fund 40% of competing applications.

Encourage investigators to commit to cancer research careers and to propose more innovative and higher risk/higher reward projects.■ Continue to allocate the first 80 to 90% of RPG funds to competing applications falling within

conventional merit rank order paylines.■ Ensure reasonable funding success rate for high risk/high reward applications and a success rate

at least equal to traditional R01 grants for applications from new investigators.

Enhance opportunities for rapid reconsideration of outstanding applications that fall just beyond established paylines. ■ Allocate up to 20% of RPG funds for meritorious applications outside conventional paylines.■ Expand AER to include Program Project Grants.

Invest in areas of special opportunity or need.■ Use regular, novel, and special award mechanisms to encourage investigation in priority areas.■ Provide staff, resources, and enhanced electronic communications to improve information

dissemination, enhance coordination within and between initiatives, and increase direct contactwith applicants and grantees.

Optimize awards to accelerate discovery.■ Fund at full peer-reviewed recommended budget levels for up to 5 years of support.■ Ensure access to NCI-sponsored resources, infrastructure, and technologies.■ Set aside funds for administrative supplements.■ Expand R03, R21, R33, and other awards to provide seed funds and resources.

Facilitate rapid movement from discovery to application through interdisciplinary and collaborative approaches.■ Use established and novel mechanisms to encourage collaborative and translational research.

Add application phase to R21/R33 Phased Innovation Award.■ Expand administrative supplements to encourage collaborations and promote access to resources.■ Expand access to resources and technologies that promote interdisciplinary research and

collaborations through centers, networks, and consortia.■ Expand cooperative resource programs (e.g., RAID, RAPID, CGAP, EDRN) to improve access to

technologies and expertise.■ Encourage development of information technology tools to expedite interdisciplinary

communication and collaboration.■ Double funding for collaborative research awards.■ Expand exploratory grants for patient- and population-based research.


TOTAL $146.0 M

THE CHALLENGE

The rapid pace of scientific and technological dis-covery has created enormous opportunities.

Along with them come some very significant chal-lenges. The most obvious one – how to turn scien-tific knowledge into more effective cure and controlof cancer – is NCI’s mission. To do this most effec-tively, the research community must first successful-ly address another challenge – one having to dowith the culture of the research community itself.

For decades, laboratory-based biological investi-gation – the “basic science” of cancer research –has flourished in the familiar departments of ourmedical schools, universities, and research insti-tutes. It has always been a kind of “cottage indus-try” in which small, cohesive laboratory groups arethe units that do the research, sometimes workingwith similar groups in ad hoc collaborations. Asbiomedical science has advanced, however, it hasbecome clear that certain kinds of scientific prob-lems cannot be addressed in this way. This haslong been the case for certain epidemiologic stud-ies and clinical and populations research, whichoften require teams of substantial size that maystraddle multiple institutions. What is really new,however, is the sheer extent to which the need for“team research” has come to pervade biology andmedicine, particularly for those problems thatrequire back-and-forth movement between thelaboratory and clinics or populations.

Multidisciplinary teams are needed to solve vir-tually all of the “big” problems in cancer research –sequencing the genome, creating the next genera-tion of sensitive and specific imaging devices, ordiscovering and testing target-specific therapeuticsand preventives. Increasingly, single institutions donot have the scientific breadth, patient resources,or regional outreach to populations to enable themto address the major scientific questions uponwhich really effective cancer control will depend.The cultural challenge to the scientific community,

therefore, is to go beyond customary ways of think-ing and organizing, beyond traditional academicdepartments and faculties, to establish whateverkinds of cross-disciplinary and multi-institutionalcollaborations are needed to get the work done.

More specifically, we need to create quite newkinds of functional links – not only among basic,clinical, and population scientists, but also acrossvery diverse fields of science and technology. Weneed productive interfaces among and betweenmathematicians, biologists, computer scientists,epidemiologists, imaging scientists, chemists,physicists, and clinicians. Similarly, as scientificand technological development provides us withnew tools to intervene at many points along theentire trajectory of malignancy, the actual testingof these new interventions – whether for preven-tion, detection, diagnosis, or treatment – willrequire the collaboration of many scientists withdiverse backgrounds. These scientists will requireaccess to many different kinds of resources, such aspatients, at-risk populations, tissue banks, newtechnologies, and state-of-the-art informatics.These many requirements will best be satisfied byspecialized networks, centers, and consortia thatincorporate diverse expertise and flexibility infunding and in administration.

For these reasons, NCI proposes to expand itsprograms for Centers of Research Excellence andCancer Centers and to develop a variety of newresearch networks and consortia. Centers can serveas platforms for developing and providing access totechnologies, for promoting and facilitating com-plex scientific interactions, and for providing thecritical resources essential for research studies ofgreat scope. NCI will enable more specializedresearch networks and consortia to develop novelcapabilities and link with NCI Cancer Centers.

NCI-designated Cancer CentersThe NCI-designated Cancer Centers are key partners in NCI’s efforts to speed the process of

Centers, Networks, and Consortia 2C H A L L E N G E


Challenges

discovery and bring the benefits of cancer researchdirectly to the public. Centers coordinate multi-disciplinary approaches to research questions, provide access to the most advanced researchtechnologies, and take rapid advantage of newresearch opportunities. Support of the CancerCenters helps ensure a close association betweenstate-of-the-art research and clinical care activitieswithin the institution. It also allows each Centerto develop key collaborations and partnershipswithin industrial, community, and state healthorganizations, and link the research capabilitiesand expertise of scientists within the institution toproblems of cancer incidence and mortality intheir communities and regions.

Establishing partnerships between andamong NCI-supported centers andresearch institutions is equally important.NCI will create Regional EnhancementCenters that will work closely with exist-ing NCI-designated ComprehensiveCancer Centers; these partnerships willprovide patients and populations withmuch improved access to studies in earlydetection, prevention, and therapeuticresearch. NCI also has recently launchedthe Special Populations Network forCancer Awareness Research and Training. Thisinitiative will develop and maintain partnershipsbetween scientific researchers and communityleaders from a broad range of minority and under-served populations. In addition, the CancerCenters will be enhanced by placing a strongeremphasis on the need for collaborations betweenthe Cancer Centers, industry, and non-traditionalacademic sites lying outside the orbit of cancerresearch. These will enable the Centers to func-tion more effectively as platforms for broad-basedearly technology development, and ensure thatthe research community can gain access to thesetechnologies.

Centers of Research ExcellenceCenters of Research Excellence are multidiscipli-nary and translational research teams focused on aspecific disease, modality, biologic process, or sci-entific area of particular significance. They areawarded sizeable amounts of flexible funding toenable them to rapidly address emerging scientificopportunities or specific challenges. NCI’s SPORE

program (Specialized Programs of ResearchExcellence) is one highly successful example of thisapproach. Each SPORE group focuses on a specificcancer site. Their goal is translational: they aim tomove discoveries and observations back and forthamong laboratory, clinic, and population settings.Research in the SPOREs focuses on approaches forreducing cancer incidence and mortality andimproving survival and quality of life. Recent find-ings from the SPORE program include the identifi-cation of several tumor suppressor gene mutationsthat lead to pancreatic cancer, and the first humangene therapy approaches for advanced prostatecancer. NCI is supporting SPOREs in cancers ofthe breast, prostate, lung, and gastrointestinal tract,

and one soon will be awarded in ovariancancer. We plan to expand the SPOREprogram to all cancer sites; each SPOREwill continue to focus on a specific cancer.

Additional examples of the centers ofexcellence concept that we have recentlyimplemented or will shortly implementinclude those in tobacco research, molec-ular and in vivo imaging, communications,population health, and interventionsdirected against molecular targets.

Consortia and NetworksMany of the most innovative ideas emerge fromgroups of scientists who link their expertise andresources to address important questions abouthuman cancer. NCI has taken steps to facilitatejust this sort of complex collaborative effort. Forexample, we recently established the CancerGenetics Network (CGN), which is dedicated tostudying inherited predisposition to cancer. TheCGN consists of eight centers and an informaticsand information technology group. It builds onrecent progress in isolating genes linked to inherit-ed cancer and promotes the application of thisknowledge to the clinical setting. The CGN notonly will integrate discoveries into medical appli-cations such as prevention, detection, and cancercontrol, but will address psychosocial, ethical,legal, and public health implications of inheritedcancer susceptibility. The Diagnostic ImagingNetwork creates, for the first time, a multi-centerresearch group to systematically evaluate newimaging technologies and their impact on cancermanagement and health care outcomes. We


For a list of

Cancer Centers

visit

http://www.

nci.nih.gov/

cancercenters/

centerslist.html

http://www.nci.nih.gov/cancercenters/centerslist.html


Challenges

expect that strong collaborative relationships willdevelop between the Diagnostic Imaging Networkand industrial device manufacturers, as well asbetween the imaging network and our clinicalcooperative groups that perform treatment andprevention studies. Networks for early detectionstudies and for developing better animal models ofhuman cancer are additional examples of special-ized consortia that the NCI recently has begun.

Centers and networks actively reinforce eachother. For example, NCI recently has supportedinnovative proposals from several collaboratingSPOREs to study the molecular characteristics ofbreast duct carcinoma in situ and to create a com-mon language and data bases that will pave theway for joint studies in lung cancer preventionand early detection.

THE GOALS

■ Refine the organizational framework of centers,consortia, and networks to stimulate and expe-dite interdisciplinary collaborations.

■ Promote collaborations among and betweenbasic, clinical, and population scientists by pro-viding the infrastructure to support a critical massof expertise and a variety of study populations.

■ Stimulate unique forms of research that can beconducted only by interinstitutional, interdisci-plinary teams of investigators.

■ Support centers and consortia as platforms fortechnology development and application.

THE PLAN

Objectives1. Increase the number and broaden the

geographic distribution of NCI-designatedCancer Centers. ■ Establish new NCI-designated Cancer Centers.■ Award new cancer center planning grants.

2. Expand NCI Cancer Center linkages toincrease their research capabilities and broaden their access to populations that currently lack access to centers.■ Create new Regional Enhancement Cancer

Centers that will collaborate with existing

NCI-designated Comprehensive CancerCenters to expand the base of patients andpopulations available for early detection, pre-vention, and therapeutic research studies.

■ Establish formal affiliations between cancercenters and minority institutions to strength-en the research capabilities of minority insti-tutions and to enable collaborative researchprograms focusing on the burden of cancer inminority groups.

■ Establish a program of competitive cancercenter supplements to foster new collabora-tions among centers, particularly when thecenters are competing for the same popula-tions or patient bases or when combiningresources can address important questionsmore effectively.

3. Expand the capacities of NCI-designatedCancer Centers to engage in newly developingareas of research that are critical to solvingthe cancer problem.■ Establish Advanced Technology Programs in

cancer centers to enable center investigatorsto access cutting-edge technology developedin industry and to develop applications andpilot projects to solve particular problems incancer research.

4. Expand the research programs in NCI’sSpecialized Programs of Research Excellence(SPOREs) and other Centers of ResearchExcellence. ■ Expand the scope of the SPORE program to

include all cancer sites. ■ Create and expand Centers of Research

Excellence to support multidisciplinary andtranslational research teams focused onmodalities, biological processes, or scientificareas of particular significance.

■ Provide supplements to SPOREs and otherCenters of Research Excellence to developand initiate complex inter-institutionalexploratory research initiatives.

■ Support the development of an Internet plat-form for SPOREs to exchange research resultsand to foster the communications needed forsharing resources and conducting inter-SPORE collaborative research.

5. Enhance the capacity of NCI Centers to actas platforms for translating discoveries intointerventions.■ Provide funding for research nurses and data

managers.■ Develop clinical trials informatics to conform

with NCI’s Cancer Informatics Infrastructure.■ Address regulatory issues.

PROGRESS TOWARD MEETING THE CHALLENGE

In the past year, NCI has taken a number of steps to strengthen and expand research support

mechanisms designed to foster multidisciplinary andmulti-institutional collaborations. These collabora-tions are bringing together diverse scientific disci-plines across institutional boundaries, improvingaccess to new technologies and patient populations.

The emergence of new and improved medicalimaging technologies is an area of cancer researchthat will depend on effective multidisciplinary col-laboration. NCI has created In Vivo Cellular andMolecular Imaging Centers that will provide theinfrastructure to foster the interaction and collab-oration of imaging scientists with basic biologists,chemists, immunologists, computer scientists, andphysicists to focus imaging research on the detec-tion of genotypic and phenotypic abnormalities inoncology. Similarly, NCI is providing support forthe Diagnostic Imaging Network to bring togeth-er imaging experts from across the country to per-form a broad spectrum of multi-institutional clini-cal diagnostic imaging trials related to cancer.

Increasingly, tobacco control and addictionresearch must rely upon scientists with expertise indiverse areas including molecular biology, genetics,neuroscience, epidemiology, imaging, behavioralscience, primary care, and communication. To fur-ther transdisciplinary research in tobacco controland addiction research, NCI and the NationalInstitute on Drug Abuse have created Trans-disciplinary Tobacco Use Research Centers.

Two areas of extraordinary opportunity identi-fied by NCI in this document are Defining theSignatures of Cancer Cells: Detection andDiagnosis, and Molecular Targets of Preventionand Treatment. Possibly no other opportunitieschallenge us to work more collaboratively inmulti-institutional settings with multidisciplinary

teams than these. As stated in the ExtraordinaryOpportunities section, new molecular-based tech-nologies are enabling us to identify features of cellsand the transformation of normal cells to cancer-ous cells in unprecedented ways. The implicationsof these discoveries for cancer detection, diagnosis,and treatment are profound. The NCI-supportedEarly Detection Research Network (EDRN), amulti-institutional network, links centers ofexpertise in tumor biology, diagnostic technolo-gies, and clinical trials methodology in academiaand industry to develop, evaluate, and validatebiomarkers for early cancer detection.

To develop and test target-based therapeuticsand preventives, NCI will create a series of multi-disciplinary research groups, each organizedaround a mechanism of particular relevance tocancer therapy, such as angiogenesis, cell cyclecontrol, immunotherapy, DNA repair, metastasis,and apoptosis. These consortia will bring togetherchemists, biologists, pharmacologists, imagers, cli-nicians, and informatics experts to create toolssuch as assays, probes, and reagents necessary toassess the effects of cancer drugs on their molecu-lar targets in patients with cancer.

Developing experimental models that mimicthe wide variety of human cancers is critical tounderstanding how a cancer gene disrupts the nor-mal processes of a cell. The challenge has alwaysbeen the lack of infrastructure to develop and dis-tribute efficiently to the research community therange of models necessary to represent human can-cer and to validate these as predictive models ofhuman cancer. NCI has undertaken a major effortto overcome these challenges by creating theMouse Models of Human Cancer Consortium, aconsortium of scientific laboratories and teams ofscientists dedicated to developing, validating, andcharacterizing mouse models of human cancer.

Other recently established or expanded NCI-sponsored consortia include the Pediatric BrainTumor Consortium, a network of medical centersthat will evaluate promising treatments for chil-dren with brain malignancies; and the Commu-nity Clinical Oncology Program and theMinority-Based Community Clinical OncologyProgram, which provide the infrastructure to linkcommunity cancer specialists and primary carephysicians with NCI’s Clinical CooperativeGroups and Cancer Centers.



Challenges

Resources: Centers, Networks, and Consortia

Broaden geographic distribution of NCI-designated Cancer Centers. $5.1 M■ Designate 3 new Cancer Centers.■ Award 3 new Cancer Center Planning Grants.

Link NCI Cancer Centers to populations. $9.5 M■ Establish 2 Regional Enhancement Cancer Centers.■ Establish formal affiliations between NCI Cancer Centers and minority institutions.■ Award Cancer Center supplements to support inter-center collaborations.

Expand capacity of NCI-designated Cancer Centers. $16.0 M■ Establish 10 Advanced Technology Programs in Cancer Centers.

Expand NCI’s Specialized Programs of Research Excellence (SPOREs) and other Centers of Research Excellence. $15.3 M■ Establish 6 new SPOREs/Centers of Excellence.■ Provide supplements to SPOREs and Centers of Research Excellence for inter-institutional

exploratory research initiatives.■ Support development of Internet platform for SPOREs.■ Support Centers of Research Excellence.1

Enhance capacity of NCI Centers to act as platforms for translating discoveries into interventions. $14.5 M■ Provide funding for research nurses and data managers.■ Develop clinical trials informatics to conform with NCI’s CII.■ Address regulatory issues.


TOTAL $62.4 M

1 See Cancer Imaging, Molecular Targets for Prevention and Treatment, Research on Tobacco and Tobacco-Related Cancers, Cancer Communications, and Studying Emerging Trends in Cancer for specific budget items.

THE CHALLENGE

The research investment of the past decade hasproduced major advances in our understanding

of tumor biology and molecular targets – thetumor-related molecules that can be selectively tar-geted to treat or prevent cancer. It also has broughtabout a dramatic increase in the number of newpreventive, diagnostic, and therapeutic agentsbeing tested in clinical trials. But our present clini-cal trials system is failing to keep pace with thegrowing number of agents that will merit testing inpeople. Currently, an estimated 354 new cancertreatments are in development by industry, a three-fold increase during the 1990s. In 1999, NCI

entered into clinical trials approximately 30 novelagents discovered through its own drug discoveryprograms or in collaboration with academic institu-tions or industry. This is in addition to 78 promis-ing new interventions for treatment and 32 for pre-vention that NCI already is testing in people.

As these potential treatments and preventionstrategies emerge from early clinical testing, NCI isfaced with a backlog of agents that need to enterlarge Phase III trials – the final crucial step in thetranslation of new discoveries into effective newtreatments and prevention strategies for patients.(See page 27 for more information.) At present,NCI and its grantees are able to initiate only about30 Phase III trials each year. Compounding this

National Clinical Trials Program3 C H A L L E N G E


Without question, our ability to prevent cervicalcancer through regular Papanicolaou screening

tests – also called the Pap smear – is a major publichealth success story in the United States and manyother countries with established screening programs.But in developing countries, few women receive thislife-saving screening, and invasive cervical cancer stillstrikes an estimated 350,000 women each year, killing200,000. And even with the success of cervical cancerscreening in the U.S., about 15,000 women each yearwill learn that they have this disease. Some olderwomen fail to be screened because they believe they areno longer at risk, or because their physicians do notrecommend screening. HIV-positive women, whoseimmune systems are weakened, are at greater risk ofinfection with the human papillomavirus (HPV) that hasbeen discovered to be the primary cause of 90 percentof cervical cancers. In addition, some populations ofwomen still avoid screening, or live in medically under-

served areas where screening rates are as low as thosein developing nations. For these reasons, population,laboratory, and clinical researchers are working to dis-cover more effective, less invasive, and less costly waysto prevent, diagnose, and treat cervical cancer here andaround the world.

Population and laboratory studies led to discovery of theHPV-cervical cancer link, and clinical studies have shownthat while sexually transmitted HPV infection is wide-spread in the population, most infections go away bythemselves within six months. Moreover, we now knowthat only a small percentage of women with HPV – eventhose infected with the HPV types most associated withcervical cancer – actually develop the disease. Further,even moderately severe cell proliferation believed to be aprecursor of invasive cancer may regress spontaneously,suggesting new approaches to monitoring and treatingthese early lesions.


Viruses, Vinegar, and Vaccines – Preventing Cervical Cancer


Challenges

problem is the fact that for a variety of reasons –e.g., limited access, lack of insurance coverage,patient-physician communication issues, therapychoice – only about 20,000 patients enter Phase IIItrials each year. Overall, fewer than three percentof patients with cancer participate in the clinicaltrials that define effective new treatmentapproaches. Thus, it can take over four years just torecruit enough patients for the average Phase IIItrial. In addition, more than 80 Phase II and IIIprevention trials have been initiated, but progressin this area is limited by lack of methods, such asbiomarkers, to determine the effect of a preventiveover a short period of time, lack of technologies toimprove precision in characterizing precancerouslesions, and the growing number and complexity oftrials needed to determine the roles of this newgeneration of agents.

How can we more efficiently convert recent sci-entific discoveries into effective interventions,eliminate the backlog of agents for testing, andincrease patient access? We must invest in, restruc-ture, and increase the capacity of our national clin-

ical trials program. NCI has reconfigured majoraspects of its clinical trials program to increase thespeed and smooth the path for entering promisingagents into trials. While the time from initiation ofclinical trials to Food and Drug Administration(FDA) approval has improved over the pastdecade, the clinical development required to estab-lish the best uses of new agents still occurs over amuch longer period. For example, paclitaxel(Taxol®), approved for use in ovarian cancer in1992, also has a potentially life-saving role in sev-eral other cancers, including cancers of the breast,lung, prostate, head and neck, esophagus, and blad-der. Even so, the clinical trials to define its use inthese diseases are still ongoing seven years afterFDA approval for ovarian cancer treatment.

The changes we propose in the following planwill substantially increase the number of trials andnumber of patients who enroll in trials each yearby easing the way for physicians to communicatewith patients and enroll them in clinical trials.The plan also calls for funding the kinds of labora-tory studies that will help determine why particular

These and other findings are leading to much-needed inter-ventions for women. A refined Pap test is slowly gainingacceptance in community practice; more cells are sampled,cell preparation errors are less likely, and the sample can besaved and reused if a reading is questionable. The new testalso is easier to read and substantially more accurate. Indeveloping nations, an easily performed screening test inwhich the cervix is swabbed with a vinegar solution thatdiscolors only abnormal cells is being studied in selectedpopulations. It could bring affordable screening to millionsof women in countries where health care resources and per-sonnel are so scarce that currently, only five percent ofwomen are screened for cervical cancer. HPV DNA testingfor women who have a questionable Pap smear shows prom-ise as a reliable, less invasive, and less costly method ofdetermining a woman’s cervical cancer risk and catchingearly disease, compared with current approaches.Prevention vaccines are being developed that will prime theimmune system to recognize both cancer-linked and otherHPV types and attack if infection occurs. If given to menas well as women, these vaccines will prevent cervical can-

cer and also may prevent sexually transmitted HPV diseaseslike genital warts that affect both genders.

There also is encouraging news for women who do developsuspicious cervical dysplasia or invasive cervical cancer. Tobetter guide the treatment of precancerous cervicalchanges, a refined and simplified system of classifyingthese early lesions – the Bethesda system – has beenestablished. Treatment vaccines that spur the immune sys-tem to attack existing HPV infection are on the near hori-zon. Of great importance, NCI recently issued a specialannouncement to physicians to inform them of the resultsof five clinical trials involving women with locally andregionally advanced cervical cancer. These trials showedthat women achieved significantly improved survival whencisplatin-based chemotherapy was given concurrently withradiation therapy – the risk of cervical cancer death wasreduced by 30 percent. Based on these definitive results,NCI strongly urges that physicians consider addingchemotherapy to the treatment of women who requireradiation therapy for cervical cancer.


drugs are effective in some patients and not in oth-ers. The results will help us tailor treatments forcancer patients in the future. These enhancementswill help speed development of agents and allevi-ate the backlog of agents awaiting evaluation.

THE GOALS

■ Create a more effective and efficient clinicaltrials system.

■ Accelerate clinical evaluation of the best scien-tific ideas and approaches for treatment andprevention.

■ Study a broader range of clinically relevantquestions.

■ Enhance collaborations between NCI, academia,industry, and other agencies in developing prom-ising therapeutic and preventive approaches.

■ Make access to clinical trials a realistic possibility for many more patients with cancer.

■ Achieve better short-term assessment of prom-ising strategies by developing and validatingmolecular and imaging risk biomarkers.

THE PLAN

Objectives1. Increase pace of development and clinical test-

ing for new therapeutic and preventive agents.■ Triple the number of promising agents enter-

ing Phase I and II clinical trials annually. ■ Implement a new rapid-review grant support

program for mechanism-based clinical trials(Quick-Trials) to support trials of novelagents and the associated laboratory studiesthat assess a drug’s effects on its target.

■ Include correlative laboratory studies in clini-cal trials to elucidate the molecular mecha-nisms of response and drug effects.

2. Address compelling clinical questions confronting physicians and patients struggling with cancer.■ Conduct disease-specific State of the Science

Meetings to bring together the Nation’s leadingmultidisciplinary experts, to identify the impor-tant research questions for a given disease andhelp define the scientific research agenda thatwill assist us in addressing those questions.

■ Sponsor clinical trials of the best scientificconcepts from individual academic sites orinvestigators, pharmaceutical or biotechnolo-gy companies, or others through NCI’snational network of cooperative groups andcommunity practice sites.

■ Provide Concept Evaluation Panels for NCIPhase III trials conducted through ournational accrual network

■ Provide scientific leadership funding to permitacademic investigators the time necessary todevelop and conduct clinical research protocols.

■ Provide funds for correlative studies to elucidate the mechanisms underlying newtreatments and preventive strategies.

■ Support the broad acquisition of tumor specimens/tumor banks to facilitate rapidevaluation of new assays and relevant clinicalcorrelations as new targets are identified.

■ Use Centers of Excellence to develop themolecular assays required to characterize/classify patient tumors.

■ Develop reference laboratories so that appropriate assays are widely available.

3. Maximize the use of existing clinical trials infra-structure to study prevention and treatment out-comes and other clinically relevant questions.■ Integrate treatment with prevention, early

detection, epidemiology, behavioral, andother relevant research areas to most effec-tively address the burden of cancer in specifictumor types and patient populations.

4. Develop common informatics systems, shareddata bases, and information resources thatallow physicians to enroll patients in trialsand report data from any site nationwide.■ Establish common data elements so that

all clinical trials are written in the same “language” and so that results can be easilycombined and compared.

■ Develop common forms and interfaces forphysicians participating in trials.

■ Create electronic protocol authoring tools tospeed protocol generation.

■ Create electronic update and reporting systems.5. Increase the number of referring physicians

and patients who participate in clinical trials.■ Create a national accrual network that allows

physicians to enroll patients in any of thePhase III trials sponsored by NCI.

■ Extend outreach efforts to physicians in busyand competitive practice settings; provide thedata management and research support theyneed to enroll their patients on clinical trials.

■ Extend outreach to minority patients andphysicians to improve their access to state-of-the-art cancer therapy.

■ Use a variety of media to increase substantial-ly the information available to patients aboutclinical trials.

■ Provide extensive electronic informationabout available treatment and preventionprotocols to physicians.

6. Create collaborations to optimize resources.■ Facilitate new partnerships with aca-

demia, industry, patient advocacygroups, professional societies, andother organizations to accomplishresearch objectives, share resources,and avoid duplication.

■ Provide opportunities for industry toinvest in and use the national clini-cal trials infrastructure to performimportant clinical trials.

7. Identify relevant biomarkers.■ Identify novel response-related bio-

markers by measuring tumor burden.■ Conduct research on molecular profiling of

cancer cells to identify patients mostlikely to benefit from specific treat-ments. Monitoring biomarkers canmore quickly identify patients with asuboptimal response who may requirea change or discontinuation of treat-ment.

■ Fund intergroup studies to evaluatebiomarkers for monitoring treatmentresponse.

8. Support intramural clinical trials.■ Support high priority clinical trials

conducted at the NIH ClinicalCenter.


In 1996, an external review group conducted anin-depth review of NCI’s clinical trials sys-

tem. The review group made major recommenda-

tions regarding review, funding, design, oversight,and administration of our clinical trials system. InSeptember 1998, a plan for implementing theserecommendations was approved. Since that time anumber of pilot projects have been initiated:■ State of the Science Meetings are being held on

prostate cancer (November 1999 and February2000), lung cancer (September 1999), leukemia(March and September 2000), and colorectalcancer (January 2000).

■ This year, Concept Evaluation Panels, expertpanels of nationally renowned scientists, were formed to review and prioritize Phase IIIclinical trials proposals in lung and genitouri-

nary cancers.■ A Cancer Trials Support Unit (CTSU)

was created to centralize administrativeand data management functions nowduplicated in numerous clinical trialsorganizations. A Request for Proposalswas issued in March 1999 with awardsplanned for September 1999.

■ New Cooperative Group peer reviewcriteria and procedures were imple-mented in March 1999.

Along with the launch of several new pilotprojects, NCI has increased funding for its

Cooperative Groups (see page 28), whichhave been funded below peer review rec-ommended levels for many years. A 29percent increase in funding was providedin 1999, reducing the gap in funding by33 percent overall.

Finally, we are implementing newinformation systems, such as an electron-ic Adverse Event Reporting System thatcaptures information on severe toxicitiesexperienced on clinical trials, and aPhysician Communication Module in col-laboration with the Howard UniversityCancer Center. This computer-based toolwill facilitate clinical trials data collec-tion, help physicians in office settingsidentify trials for eligible patients, andprovide educational information. Thisproject should increase minority physician

and patient participation in NCI clinical trials.


Challenges

For more

information on

the clinical trials

review visit

http://ctep.

info.nih.gov/

Armitage/

For more

information on

clinical trials

implementation

visit

http://

cancertrials.

nci.nih.gov/

NCI_CANCER_

TRIALS/zones/

Tools/Booklets/

Plan/index.

html

http://ctep.info.nih.gov/Armitage/

http://cancertrials.nci.nih.gov/NCI_CANCER_TRIALS/zones/Tools/Booklets/Plan/index.html


Accelerate new agent development and clinical testing. $121.8 M■ Increase funding for Early Therapeutics Development contracts.■ Implement Quick-Trials.■ Establish Centers of Excellence in interventions directed to molecular targets.■ Establish Translational Research Fund for correlative laboratory studies in clinical trials.■ Establish Group Developmental Fund to support Cooperative Group pilot correlative studies.■ Provide adequate funding to Cooperative Groups and practice sites for data management

and to double or triple physician participation in clinical trials.■ Provide information about treatment and prevention options and clinical trials needed to

enable patients and physicians to make informed treatment choices. (See Informatics)■ Increase contracts for prevention drug development; accelerate patient accrual to prevention trials.

Address the most compelling clinical questions. $31.6 M■ Conduct State of the Science meetings for genitourinary and lung cancers.■ Establish Concept Evaluation Panels for NCI Phase III trials.■ Provide Scientific Leadership Funds to study chairs and statisticians who write, monitor, and

analyze high priority Phase III trials approved for conduct in the national accrual network.■ Fund correlative studies to elucidate and translate basic biology from bench to bedside.■ Fund tissue banks to store tissues from patients in studies of drug effects, molecular abnormalities

in tumor and normal tissue, and tumor initiation and progression mechanisms.

Maximize use of existing infrastructure. $5.0 M■ Conduct multidisciplinary meetings to explore possible Cooperative Group studies.■ Involve multidisciplinary planning teams from NCI Divisions in State of the Science meetings. ■ Increase the number of CCOPs to increase prevention clinical trials capacity.

Develop common informatics systems, shared data bases, and resources. $.0 M(Budgeted in the Informatics Challenge.)

Increase number of physicians and patients participating in clinical trials. $9.0 M■ Expand Participation Project to enable new participating physicians, including new minority

physicians, to hire the necessary research nurses and data managers.■ Establish CTSUs to consolidate administrative tasks associated with conducting clinical trials.■ Use Physician Communication Module to provide protocol and patient education information.

Create effective collaborations.■ Encourage pharmaceutical/biotechnology industry to submit concepts for high priority

Phase III trials to Concept Evaluation Panels; conduct trials through the national accrual network; and invest in CTSUs to reduce administrative redundancy.

■ Encourage private foundations and other government agencies to co-fund clinical trials.

Identify relevant biomarkers. $3.0 M■ Identify novel response-related biomarkers.■ Conduct research on molecular profiling of cancer cells to predict treatment response. ■ Fund intergroup studies to evaluate biomarkers of treatment.

Support intramural clinical trials. $25.0 M■ Support high priority clinical trials conducted at the NIH Clinical Center.


TOTAL $201.4 M

Resources: National Clinical Trials Program


Challenges

Informatics and Information Flow 4C H A L L E N G E

THE CHALLENGE

A round the globe, cancer researchers are bene-fitting from advances in computing and

telecommunications that, coupled with the explo-sive growth of the World Wide Web, help makeunprecedented research opportunities possible. Asnever before, these advances in technology enablescientists to collaborate and to generate incredibleamounts of information – the raw data from whichknowledge is created. But vast amounts of knowl-edge that already exist often go unused due to aninability to access and organize information fromdiverse sources. Therefore, we must ask ourselves,how do we best collect, manage, and share thisinformation?

The answer to this question lies in knowledgemanagement – in designing a framework to helpcapture, analyze, apply, and reuse knowledge tomake possible faster, smarter, and better applica-tions. This framework will serve as a tool to createan interface among the research communities –basic, translational, clinical, and population-based –that participate in the research discovery process.NCI is addressing the challenges presented by therevolution in electronic communications and com-puting by developing a knowledge management sys-tem – a Cancer Informatics Infrastructure (CII) –that will unify these research communities.Employing knowledge management will reducedrastically the time and effort needed to create anduse existing or new information, making researchdiscoveries possible at a scientist’s desk, in additionto the lab. By speeding the discovery process andtranslation of the best discoveries into clinicalinterventions, the CII will transform cancer carethrough more effective and efficient informationexchanges among all involved in cancer research.Finally, a knowledge management system will createnew synergies within and among the fields ofresearch described in this document, resulting in adramatic acceleration of our progress against cancer.

The first step being taken by the CII project isdeveloping a knowledge management system toincrease the speed with which we carry out clini-cal trials in cancer prevention, diagnosis, andtreatment. We are revising our criteria and stan-dards for reporting all data collected during a clin-ical trial, and are developing common forms, ter-minology, and reporting requirements across alltypes of clinical trials. This uniformity willincrease the speed, efficiency, and accuracy ofresults reporting. Special data bases of medical andscientific terminology will help researchers, clini-cians, and other users of NCI information systemsto find and understand the information they seek.The accomplishments achieved in developingthese common definitions can be applied to allareas of the research discovery process to acceler-ate scientific discovery. Once in place, the compo-nents of the clinical trials knowledge managementsystem will be applied in the basic, translational,and population-based research fields to manageinformation and share knowledge within andamong these communities.

By investing in the CII and its broad public-private partnerships, we have the opportunity tofundamentally improve our clinical trials systemand establish an infrastructure that supports com-prehensive knowledge management across diverseresearch disciplines. NCI’s leadership in this areawill enable us to establish a national clinical trialseffort that realizes maximum benefit from theinformation revolution through increased patientaccrual, common reporting practices, and greatersharing of knowledge with the public and theresearch community. We must work quickly toestablish this infrastructure, however, as industrialand academic institutions are investing individual-ly in automated systems to speed discovery, lowercosts, and capture data electronically. As individualsystems are established, it will become increasinglydifficult, and eventually impossible, to institute acommon knowledge management system. The CII

will help us address the issue of compatibility,enable us to manage the explosive growth in fun-damental discoveries, and help alleviate the seriousbottleneck that exists between discovery and itsapplication for the benefit of patients with cancer.

THE GOALS

■ Create a common infrastructure that enablescancer research through enhanced informationand resource exchange among researchers, cli-nicians, and the public.

■ Reduce the barriers experienced by patients,survivors, families, at-risk individuals, andphysicians seeking information about cancerprevention, diagnosis, and treatment.

THE PLAN

Objectives1. Design an information infrastructure and

enhance information exchange to accelerateadministration of the full range of clinicalresearch activities.■ Develop a comprehensive clinical trials infor-

matics infrastructure that ensures data com-patibility and access, enhances clinical trialsrecruitment, and promotes scientific knowl-edge exchange among all participants.

■ Develop an electronic Protocol AuthoringToolbox that contains clinical trials “buildingblocks,” including a comprehensive set ofclinical trials templates, to reduce the timeneeded to create a new protocol.

■ Develop a common, on-line protocol reviewprocess for all clinical trials that will “shep-herd” approved concepts through the approvalprocess within three months of submittal.

2. Ensure widespread availability of all types of cancer information.■ Create a usable, comprehensive cancer

information system for the public using thePDQ redesign as a model.

■ Encourage voluntary electronic submission ofinformation on non-NCI sponsored clinicaltrials to PDQ.

■ Streamline and automate research results andclinical trials information management.

3. Extend the informatics infrastructure devel-oped for clinical trials to basic, translational,and population research.■ Apply the information gained and processes

used to achieve common data definitions tothe areas of extraordinary opportunity.

■ Create mechanisms that foster interactionbetween the public and private sectors forjoint development of these informatics infra-structures and knowledge exchanges acrossthe cancer research discovery enterprise.

4. Create a knowledge management system forcancer research information and resources.■ Establish an NCI-wide approach to knowl-

edge management encompassing the widearray of scientific and resource-related infor-mation generated through NCI research.

■ Develop an inventory of research tools topublicize and enhance the accessibility of sci-entific tools and technologies developed byNCI that are useful and available to thebroader scientific community.

■ Develop a document management/workflowapproach that streamlines the review andaward process and portfolio management ofall funding mechanisms.

■ Provide necessary staffing and contract sup-port to establish the labor infrastructure nec-essary to accomplish the stated objectives.

PROGRESS TOWARD MEETINGTHE CHALLENGE

The CII project already is developing severalcomputer-based components of its clinical tri-

als knowledge management system to help cap-ture, analyze, apply, and reuse knowledge generat-ed through clinical trials. Components designed tohelp capture and manage data include:■ Clinical Trials Informatics System. Developed

by NCI, this system provides point-of-care datacollection, document management, and digitaldocument capabilities. It links all phases of theclinical trial life cycle, from protocol develop-ment, patient recruitment and screening, andprotocol implementation to publication of trial results.


Resources: Informatics and Information Flow

Accelerate the full range of cancer research activities via enhanced $25.0 Minformation exchange across a common infrastructure. ■ Complete data models of the Common Data Elements for interventional and cancer control trials

in breast, prostate, lung, gastrointestinal, and gynecologic cancers.■ Use Common Data Elements in all NCI-sponsored clinical trials by cooperative groups,

cancer centers, and the FDA.■ Implement a Protocol Authoring Toolbox to reduce time needed to create a new protocol. ■ Increase the number of on-line protocol submissions.■ Implement an on-line review and approval process for electronically submitted protocols.

Ensure widespread availability of all types of cancer information. $20.0 M■ Implement the user-friendly version of PDQ.■ Submit at least 80% of non NCI-sponsored trials on-line to PDQ.■ Implement the comprehensive cancer information system.

Extend informatics infrastructures developed for clinical trials to basic, translational, and population research. $15.0 M■ Extend data models and definitions for clinical trials to genomics, molecular targets, and

preclinical models of cancer.■ Implement 2 Research Partnership Platforms that use the CII for knowledge management.

Create a knowledge management system for cancer research information and research resources. $7.0 M■ Implement an automated application and portfolio management system. ■ Publish an inventory of research tools.


TOTAL $70.0 M

■ Clinical Data Update System (CDUS). Thissystem achieves rapid, accurate, and secure cap-ture of clinical trial data with minimal effort.CDUS successfully captures the majority of trialdata within hours of submission – a process thatpreviously took months.

■ Common Toxicity Criteria InteractiveApplication (CTC-IA). This application iden-tifies and grades adverse events experienced onclinical trials. An application is being devel-oped to capture toxicity data at the patient’sbedside to minimize errors and duplication.

■ Adverse Events Reporting System. This sys-tem complements the CTC-IA and collectsinformation on severe toxicities experienced onclinical trials to assure future patient safety.

■ Clinical Trials Monitoring Branch AuditInformation System. This system assists NCIand cancer researchers in ensuring the qualityand scientific integrity of NCI-sponsored trials.

Additional CII components facilitate the proto-col submission and approval process for clinicaltrials and help pharmacists manage, order, andtrack NCI investigational agents. Finally, we arecreating common data elements that will simplifyand standardize data collection for cancer trials.

NCI is also redesigning the Physician DataQuery (PDQ) – its comprehensive cancer informa-tion data base – based on substantial usability test-ing to make the information in it more accessibleand easier to navigate for all users. The new PDQUniversal Database stores any type of cancer-relat-ed information – images, sound, movies, and text– and delivers data in a wide variety of media.


Challenges

THE CHALLENGE

C ancer surveillance – identifying and trackingtrends in our national cancer burden, and

monitoring the factors that influence thesechanges – is a crucial underpinning of our effortsto prevent and control cancer. Unequivocally, weare making real progress against cancer, and reduc-tion in the cancer burden on people is a criticalmeasure of that progress. Between 1990 and 1996,cancer incidence and death rates dropped for allcancers combined and for most of the top 10 can-cer sites, reversing a decades-long trend of risingcancer incidence and death in the United States.These decreases are hard evidence of the wisdomof this Nation’s investment in cancer research.

Appropriate decision making in sci-ence and in public health depends onaccurate, reliable information about theincidence and impact of disease.Established in 1973, NCI’s Surveillance,Epidemiology, and End Results (SEER)cancer registry program has been a worldmodel for tracking population trends incancer morbidity and mortality The NCIcancer surveillance program uses SEERdata to identify and study trends, trackthe impact of cancer on the general population,and provide information that researchers need toask critical questions about why certain popula-tions are affected by cancer more severely thanothers. SEER data have enabled us to identifyenvironmental carcinogens, track cancer-relatedeffects of tobacco on men and women, identifygeographic areas with higher than average cancerrates, study patterns and outcomes of cancer care,and identify risk groups for research and publichealth intervention programs.

Recent changes in health care financing anddelivery, the revolution in informatics and com-puter programming technology, and the social andcultural diversity of our country present new chal-

lenges and opportunities in surveillance research.Currently, our understanding about how risk fac-tors, screening, and treatment may affect trends inthe cancer burden is limited, and advancing ourknowledge in these areas will require new datasources and statistical methods. To more fullyassess the Nation’s cancer burden, we need dataon patterns of care and quality of life outcomes, inaddition to the incidence, survival, and mortalitydata now collected. Research is needed to improvemethods for measuring quality of life, quality ofcare, health status, morbidity, family history, can-cer risk behaviors, screening, and treatment aswell as methods and models for relating variablesand predicting outcomes. In addition, new invest-ments are required to support the adoption of

methodologic tools that will improve theprecision and expand the reach of ourcancer surveillance efforts. These toolsinclude geographic information systemsthat allow data linkage by geographiclocation, new approaches to modelingtrends, and more refined cancer maps forassembling, analyzing, and disseminatingcancer surveillance data.

NCI’s surveillance efforts should beexpanded to cover a broader spectrum of

the racial, ethnic, socioeconomic, and culturaldiversity of our country. For example, certainminorities and medically underserved populationsare not fully represented in SEER registries; thesegroups include American Indian and AlaskanNatives, rural whites and African Americans, andHispanics of Caribbean origin. New investments insurveillance research on specific population groupssuch as these will make it possible to connectinformation on prevention, risk factors, screening,treatments, and patterns of care with outcomessuch as incidence, quality of life, and survival.

Greater efforts are needed to disseminate theresults of NCI’s surveillance research to policymakers, advocacy groups, and the general public.

Studying Emerging Trends in Cancer5 C H A L L E N G E


For more

information on

SEER visit

http://www.

seer.ims.nci.

nih.gov/

http://www.seer.ims.nci.nih.gov/


Challenges

In addition, we must improve our ability to pro-vide epidemiologists and other population-basedinvestigators with the information crucial todeveloping new ideas for research on cancer’scauses and developing interventions based onstudy findings. As the field of surveillance researchexpands and takes on these new challenges, it isclear that scientists with skills that encompass thedisciplines of epidemiology, statistics, disease regis-tration, geographic information systems, and infor-matics are in short supply. To strengthen thismaturing scientific discipline and ensure that wehave the data we need to guide cancer researchactivities of all types, we must create the trainingopportunities necessary to prepare the next gener-ation of surveillance researchers. Finally, enhanc-ing our investment in surveillance research willensure that NCI continues to play an active andvisible national leadership role in developing acomprehensive national surveillance program.

THE GOALS

■ Improve our ability to describe the cancer bur-den across a broader spectrum of the population,track changes in cancer rates, and explainobserved changes in trends by their relationshipsto changes in risk factor and screening data.

■ Enhance the value of the surveillance system asa research resource by including treatmentmeasures and genetic studies.

■ Improve and expand communications relatingto cancer surveillance and trends to researchers,public health professionals, advocates, legisla-tors, policy makers, and the public.

■ Ensure a cadre of skilled surveillance researchers. ■ Foster interdisciplinary studies within the

population-based sciences to increase opportu-nities for applying new discoveries to improvepublic health.

THE PLAN

Objectives1. Expand studies to improve our understanding

of the experience of cancer survivors, includ-ing patterns of care people receive, quality oflife they experience during and after treat-

ment, and influence of various modes ofhealth services delivery on their outcomes. ■ Support initiatives to expand patterns of care

and outcome studies among cohorts ofpatients with specific types of cancer.

■ Initiate prospective cohort studies to monitorcommunity practice patterns for screening,diagnosis, treatment, and health-related out-comes of men with prostate cancer.

■ Fully develop and staff a program in canceroutcomes research.

■ Develop the infrastructure needed to collabo-rate with our national partners in cancer sur-veillance to find better ways to measure can-cer care quality across all populations.

2. Improve our ability to connect data on cancerrisk factors (i.e., lifestyle behaviors and envi-ronmental exposures) and screening practiceswith cancer outcomes in defined populationswith high quality cancer registration systems. ■ Expand the Breast Cancer Surveillance

Consortium.■ Support a Colorectal Cancer Surveillance

Consortium.■ Support initiatives for continuing method-

ologic linking studies.3. Expand SEER data collection to include

underrepresented U.S. population segments,including rural whites, rural AfricanAmericans, Hispanics of Caribbean origin,Alaskan Natives and American Indians. ■ Support feasibility studies for adding two to

five new SEER areas (e.g., states, regions);provide technical assistance/quality controlfor seven to 21 non-SEER regions to enablethem to meet national registry standards.

■ Fund selected high quality, non-SEER reg-istries for special surveillance studies.

4. Create opportunities to develop and sharemethodologic tools for assessing, analyzing,and disseminating data. ■ Support studies of modeling methods.■ Accelerate in-house development of measures

of risk and screening for surveillance.■ Support studies incorporating geographic

information system methods for surveillance.■ Support initiatives to develop new maps of

the cancer burden and its determinants.

5. Enhance the SEER program by initiating thecollection of family history data and biologicspecimens from cancer patients, and by incor-porating new mechanisms that allow investi-gators to rapidly identify new cancer patients. ■ Support feasibility studies for collecting

biospecimens and assessing the U.S. preva-lence of major familial cancers.

■ Support activities to expand the use of rapidcase ascertainment methods.

6. Develop new informatics initiatives for sur-veillance data on cancer patients to be collect-ed and disseminated rapidly but confidentially. ■ Support pilot informatics systems.

7. Improve the dissemination of NCI’s surveil-lance research results to researchers, policymakers, advocacy groups, and the public. ■ Produce an annual “report card” to improve

dissemination of data on the cancerburden.

■ Develop mechanisms to make sur-veillance information more readilyavailable to the academic researchcommunity and more compelling tothe public.

■ Increase development and dissemina-tion of surveillance data bases forcancer research.

■ Make new products available (e.g.,cancer maps).

8. Create cancer surveillance researchtraining opportunities to support the growingneed for skilled scientists with expertise in epi-demiology, statistics, disease registration, geo-graphic information systems, and informatics. ■ Develop and fund training programs for a

new generation of surveillance researchers.9. Create and support Centers of Excellence for

interdisciplinary studies in population-basedsciences to move basic cancer research find-ings into population research and increaseopportunities for applying discoveries toimprove public health.■ Support an initiative to create Centers for

Population Health to integrate epidemiolog-ic, behavioral, and surveillance research inareas of the country with SEER-quality can-cer registry programs.


The Plan put forth complements and extends recommendations of the Surveillance

Implementation Group (SIG), a review committeecreated by NCI to determine what cancer surveil-lance research is most needed and how best toadvance our knowledge of cancer. The SIG, whichincluded 42 leading scientists and experts fromNCI, other Federal agencies, and the extramuralcommunity, was asked to identify research direc-tions and priorities and to produce an implementa-tion plan that represented a comprehensive,focused vision for NCI-supported surveillanceresearch. In 1999, the SIG produced a CancerSurveillance Research Implementation Plan. Itidentifies five priority areas and 12 recommenda-

tions for opportunities in the study of can-cer trends.

NCI support through SEER for thePatterns of Care and the ProstateCancer Outcome studies is enhancingour knowledge about the outcomes of can-cer treatment, including quality of careand quality of life issues. In addition, theProstate Cancer Outcome Study, whichoversampled black and Hispanic men, willprovide us with much-needed informationon these population groups.

The Breast Cancer SurveillanceConsortium supports eight sites throughout theU.S. that assess accuracy, cost, and quality ofscreening programs and their impact on cancerdiagnoses and survival. Recompetition for thisprogram will continue research support and allowfor collection of more detailed risk factor data. Italso will provide an opportunity for adding othersites that provide screening for ethnic minorityand medically underserved populations.

SEER investigators and NCI staff are develop-ing a cancer survival monograph for publication in2000. It will reflect enhanced data collection andreporting on survival among ethnic minorities andthe medically underserved.

A new program called the Cancer Interventionand Surveillance Modeling Network (CISNET)is in development. Modeling is the use of mathe-matical and statistical techniques to integrate andsynthesize known biological, epidemiological, clin-


For more

information

on surveillance

implementation

visit

http://dccps.

nci.nih.gov/

DCCPS

http://dccps.nci.nih.gov/DCCPS/

ical, behavioral, genetic, and economic informa-tion. Modeling techniques have been used todescribe the impact of cancer interventions (i.e.,screening and treatment) on hypothetical cohorts(groups), or in trial and other clinical settings.CISNET will promote the application and exten-sion of these models to population-based settingsto help answer “why” questions in the analysis ofcancer trends.

Early progress is being made in working withcancer surveillance partners to develop a National

Cancer Surveillance Program. Efforts have inten-sified in the past year to disseminate public usetapes of SEER data, various software packages suchas SEER*Stat, and a broad range of CancerSurveillance Research Program resources throughthe World Wide Web. Finally, the SEER programis working with Oxford University Press on itsCancer Spectrum project to make cancer statisticsmore widely available through its on-line Journalof the National Cancer Institute.


Challenges

Resources: Studying Emerging Trends in Cancer

Collect additional data on cancer patients. $8.7 M■ Conduct quality of care studies.■ Conduct SEER special studies.■ Implement Cancer Research Network project.

Connect risk factor and screening data. $12.0 M■ Fund a Colorectal Cancer Surveillance Consortium.■ Expand the Breast Cancer Surveillance Consortium.■ Continue linkage studies.

Expand SEER coverage. $11.3 M■ Add 2-5 registries.■ Provide technical assistance for allied/pooled data registries.■ Support special studies.■ Provide technical assistance and quality control for infrastructure. ■ Enhance biomedical computing capacities.

Expand methodologic studies. $6.0 M■ Develop methods (e.g., CISNET).■ Develop measures for risk factor assessment.■ Improve outcomes methods and modeling.■ Use Geographic Information Systems and mapping.

Enhance SEER as research resource. $2.3 M■ Enhance data collection on self-reported family history of cancer.■ Develop biospecimen resource for surveillance.■ Expand use of rapid case ascertainment methods.

Develop new informatics initiatives. $1.5 M

Improve surveillance data dissemination. $0.8 M

Create surveillance research training opportunities. $1.0 M

Establish Centers for Population Health. $10.0 M


TOTAL $56.6 M

THE CHALLENGE

Training, education, and career development ofthe next generation of cancer scientists is one

of our most important challenges. Scientists of thefuture will need to both assimilate and create newmodalities and ways of thinking to keep up withthe rapid pace of scientific discovery and techno-logic advances. We will need a cadre of scientistswho can use new research models to expedite thetranslation of basic scientific discoveries intointerventions and treatments for people with can-cer or those at risk. Preparing the cancer researchscientists of the future is a long-term challengethat requires us to implement new concepts andmultiple strategies, and to make targeted, sus-tained investments to move beyond the limita-tions of traditional research establishment cul-tures, health care financing constraints, andsocioeconomic inequities. We must sustain thebasic science that enables us to discover themolecular reasons that normal cells become can-cerous. We also must harness the potential of newscientific disciplines such as informatics and inno-vative technologies for characterizing criticalgenetic and cellular functions. We must train sci-entists who can translate these discoveries intopublic benefit.

Scientists who work in different kinds ofresearch settings (e.g., laboratory, clinic, commu-nity) must have training across these disciplines sothey can take maximum advantage of every oppor-tunity for translating discovery into real advancesin cancer prevention, detection, diagnosis, treat-ment, and quality of life. Traditional administra-tive divisions that separate academic areas in theeducation and training of basic biological scien-tists, clinical scientists, public health scientists,and behavioral scientists can be diminished byemploying more unified concepts. New ways ofeducating, training, and developing scientists arenecessary to ensure that technology advances are

integrated rapidly into the cancer research enter-prise and that scientists are better prepared towork collaboratively in team settings to unravelthe complex factors contributing to human cancer.

Moreover, we cannot afford to lose a generationof talented new cancer researchers, or fail toattract established scientists to the cancer researchendeavor. Delaying investment in programs thatensure the essential training of our cancer researchworkforce of the future will cause a critical gap inthe momentum of scientific discovery.

Five crucial issues must be addressed to meetthis challenge. First, while the pool of basic scien-tists is of the highest quality, few are conductingresearch directly related to human cancer. Wemust train and encourage more basic scientists tocollaborate with clinical and population scientists.Second, the economics of the health care systemare forcing clinical investigators away fromresearch into revenue-generating care. We mustdevelop better ways to train clinical investigatorsand we must ensure that our highest quality med-ical scientists have protected time (i.e., timereserved from clinical and administrative responsi-bilities) to conduct the research that will producebetter methods of cancer diagnosis and treatment.Without a well trained and supported critical massof clinical investigators, many of the most impor-tant opportunities in patient-oriented, translation-al research will go untested. Third, the number ofpopulation scientists with sufficient professionalstability who conduct early detection, epidemiolo-gy, prevention, control, risk factor, and behavioralresearch is inadequate to sustain a high qualitytranslational research enterprise. We must developbetter ways to train population scientists in thenew interdisciplinary paradigms and increase thenumber of scientists who work in these fields.Fourth, the involvement in cancer research of sci-entists practicing in or from medically underservedareas and populations, and of underrepresentedracial and ethnic minority backgrounds, is inade-

Training, Education, and Career Development6 C H A L L E N G E



Challenges

quate. We must develop new, more effectivestrategies for attracting and training these individ-uals as scientists. Fifth, new, more powerful tech-nologies, new disciplines, and improved bioinfor-matics infrastructures are likely to be critical driv-ing forces for progress in the future. We mustdevelop new career paths that effectively linkthese areas to the cancer research enterprise.

THE GOALS

■ Build and sustain a critical mass of basic, clini-cal, population, and behavioral scientists capa-ble of taking full advantage of the vast spec-trum of future cancer research opportunities.

■ Create models for educating and training scien-tists to interact effectively in translating basicknowledge into productive cancer prevention,detection, diagnosis, and treatment strategies.

■ Attract into cancer research scientists whoseunique disciplinary orientations and/or specialtechnical skills can be integrated with those ofmore traditionally trained scientists in biologyand medicine to generate novel, more powerfulapproaches to cancer research.

■ Increase the participation in cancer research ofunderrepresented racial and ethnic minorityscientists and scientists from medically under-served areas and populations.

THE PLAN

Objectives 1. Provide a continuum of training and career

opportunities and protected time for researchfor developing and established cancer scientists.■ Sustain an active, vibrant National Research

Service Awards (NRSA) program to trainpredoctoral and postdoctoral basic scientiststhrough traditional institutional and individ-ual awards.

■ Increase participation of clinically trained indi-viduals in basic research and clinical trialsresearch through special individual “men-tored” awards; provide transition awards thatafford protected time for junior scientists todevelop their own research programs, and forsenior scientists to do research and mentoring.

■ Expand the number of well-trained populationand behavioral scientists in cancer research byexploiting the NRSA program, increasing thenumber of individual “mentored” awards, pro-viding transition awards for junior scientists,and providing senior scientists with protectedtime to do research and mentor new scientists.

■ Use resources of the NCI Intramural ResearchProgram in collaboration with extramuralinstitutions to (1) enable new scientists to useNCI’s on-campus resources to develop inde-pendent research programs (i.e., the NCIScholars Program) and (2) develop a criticalmass of mentors and expertise for training andcareer development in areas in which fewinstitutions have the full range of capabilities(e.g., prevention, radiation oncology).

■ Increase access to training and career develop-ment for basic, clinical, population, and behav-ioral scientists by improving the NCI Internetinformation services, linking NCI opportunitiesto those of other funding agencies and profes-sional organizations, and participating moreactively at national professional meetings.

2. Provide special training and career developmentopportunities that prepare new scientists tofunction in collaborative, team research settings. ■ Prepare more basic scientists who will pursue

research relevant to human cancer and whoare able to work effectively with clinical andpopulation scientists.

■ Expand institutional oncology career devel-opment programs that prepare clinically trainedindividuals to become expert in clinical trialsdesign and implementation requiring collabo-ration with basic scientists.

■ Implement new programs for population andbehavioral scientists that will prepare them towork in collaborative, team research settingswith basic scientists and clinicians.

3. Develop partnerships with academic institutions,industry, and other Federal and non-Federalorganizations for general and specialized training.■ In academic institutions, enhance the role of

NCI Cancer Centers in developing andimplementing unified cancer research curric-ula across all of the biomedical, public health,and social science disciplines; use educationgrants to promote short-term research experi-ences in multiple research settings.

■ Develop new training programs linking infor-matics to the biomedical sciences in collabo-ration with the National Library of Medicineand the National Science Foundation.

■ Create exchange programs that encourageNCI career award recipients to spend part oftheir training experience in industry to pro-mote academic/industrial collaborations.

■ Establish National Forums for short-termcourses in areas of emerging scientific impor-tance (e.g., technology, genomics) that pro-vide didactic and “hands-on” experiences to abroad range of biomedical cancer researchers.

■ Improve communication of informationabout NCI training and career developmentprograms to the Nation’s graduate schools,medical schools, and schools of public health,including minority and minority-servinginstitutions.

■ Create a seamless information continuum byelectronically linking NCI information sys-tems with those of other Federal and non-Federal funding organizations.

4. Integrate new technical and research disci-plines into the cancer research enterprise.■ Develop and implement new institutional

training instruments that can be used to inte-grate traditional biomedical researchers withother non-traditional sciences (e.g., physics,engineering, computer science) and technol-ogy developers.

■ Create the individual Diversified SciencesCareer Development Award for established sci-entists in non-traditional cancer research areaswho wish to switch to cancer research careersand work in multidisciplinary research settings.

5. Implement programs to recruit underservedethnic and minority individuals into cancerresearch, help them begin training earlier intheir education and career, and help sustainthese individuals through each stage of careerdevelopment until a high proportion are suc-cessful independent investigators.■ Implement the Continuing Umbrella of

Research Experiences (CURE) program thatprovides a continuum of training and research

opportunities, beginning in high school andcontinuing through undergraduate, graduate,postdoctoral, and junior faculty levels.

■ Link CURE to complementary programs ofother funding agencies and professionalorganizations, such as the National ScienceFoundation and the American Associationfor Cancer Research.

■ Increase the participation of minority andminority-serving institutions in cancerresearch, training, education, and outreach bysupporting the establishment of long-termpartnerships with NCI Cancer Centers andCommunity Clinical Oncology Programs.


During the past year, NCI developed a strategicplan for research training and career develop-

ment. The plan is a blueprint for meeting most ofour training and career development objectives inthe basic, clinical, population, and behavioral sci-ences in the next decade. Progress toward meetingthis challenge has been significant but will requireconcentrated attention for five years or morebefore all of our critical objectives are satisfied.

NCI has created clear career tracks offering acontinuum of opportunities that stabilize thetraining and career development of basic scien-tists, M.D.s pursuing basic science careers, M.D.spursuing clinical science careers, individuals pur-suing population science careers, individuals work-ing in or from underserved areas, and individualsfrom underrepresented racial and ethnic minoritygroups pursuing cancer research careers. Careertracks are strategically linked by individual “men-tored” awards, bridging awards, transition awards,established investigator awards, and institutionalprogram awards. NCI’s most recent progresstoward achieving its training, education, andcareer development objectives include establishingthese career tracks and implementing the strate-gies described below.


Individual Awards■ A spectrum of Individual “Mentored” five-year

award opportunities now are in place for M.D.spursuing basic or clinical science career tracksand for individuals pursuing a population sci-ence career track.

■ Bridging Awards have been created to helpbasic scientists and minorities successfully navi-gate the transition from a mentored scientist toan independent junior faculty position. Theseawards incorporate the concepts of “transition”and “protected time” for basic scientists whocommit to a research career focused on humancancer or for minority scientists pursuing acareer in any aspect of cancer research.

■ Transition Awards are three-year awards thatprovide protected time for new investigators toinitiate successful research programs. They noware in place for NCI’s two most vulnerable andcritical areas of need: medically trained doctorsin basic or clinical research, and population sci-entists. A transition award is being developedfor minority scientists.

■ Established Investigator Awards allow sea-soned investigators to set aside up to 50 percentof their salary toward protected research timeand to participate in mentoring new scientists.Those who already have independent researchsupport can qualify for up to five years of fund-ing with another five years renewal throughthis award. This award is in place for M.D.s inthe clinical science career track. This has beenNCI’s greatest priority as so many clinicians aremigrating from research to patient care in thecurrent health care delivery system. Anotherestablished investigator award is being devel-oped for the population sciences career trackand should be in place within a year.

Institutional Awards■ Institutional Program Awards are five-year

awards to institutions that select candidates forparticipation in programs designed specificallyto train individuals to work in translationalresearch and/or team research settings. Theapplications are evaluated based on the qualityof the training program and the quality of the

mentors who will participate. Of these awards,the R25 education and career developmentinstitutional grant is unique and specific to theNational Cancer Institute. It will be immedi-ately important to the prevention, control, pop-ulation, and behavioral sciences but can beapplied to all types of specialized interactivetraining programs in the future.

■ Diversified Sciences Career DevelopmentAwards are in the planning stages. They will bedesigned to attract scientists from different dis-ciplines to cancer research and to help buildteams of scientists who will work together toask and answer complex questions about cancer.

■ A spectrum of minority supplements is nowavailable. Combined with the Minority CareerAwards and Transition Awards, these supple-ments make up the new NCI ContinuingUmbrella of Research Experiences (CURE)program. This unique NCI program will attractyoung individuals from underserved areas andpopulations, and underrepresented racial andethnic minority groups into research beginningat the high school level and follow them proac-tively through each stage of their careers untilthey become independent investigators.

■ Minority Institution/ NCI Cancer CenterResearch, Training, Education, and OutreachPartnerships will be initiated. The purpose ofthese partnerships will be to increase and stabi-lize the participation of minority and minority-serving institutions in the cancer effort. Theexpectation is that these partnerships will havea major influence on the way NCI CancerCenters conduct outreach and education inunderserved communities and on the waysminority institutions conduct cancer researchand train future cancer scientists.

These career tracks and training strategies, now being planned and implemented along withimproved Internet communications and anincreased NCI presence at national meetings, will ensure that all training, career development,and education opportunities are employed fully by the scientific community.


Challenges


Resources: Training, Education, and Career Development

Provide a continuum of training and career opportunities. $27.5 M■ Support an array of career development awards and training programs for basic, clinical,

population, and minority scientists, and for diversified sciences:

20 K01 (Temin Award – basic scientists working on human disease)22 K22 (12 clinical and 10 population scientists)20 K24 (clinical science)10 K07 (population science)10 K05 (population science)24 K01 (translational research)5 K25 (high technology)2 K12 (institutional awards for clinical science; 10 positions each)5 R25 (institutional awards, 3 in population science and 2 in diversified sciences,

each with multiple positions)

118 New Awards in FY 2001

■ Create new training programs and enhance existing programs that use NCI Intramural Research Program resources (6 new scientists, NCI Scholars Program; 1 new intramural/extramural training program)

Expand training and education opportunities. $11.0 M■ Establish 2 National Forums for short-term courses in areas of emerging scientific importance.■ Develop 2 new co-funded cancer research training models.■ Create exchange programs that encourage NCI career award recipients (100 awardees annually)

to spend part of their research training experience in other research settings.

Recruit and retain more individuals from underserved populations and underrepresented racial and ethnic minority populations. $11.0 M■ Provide supplements to NCI Cancer Centers for 100 minority high school and

undergraduate students.■ Provide supplements to Research Project Grants for an additional 12 minority scientists.■ Provide supplements to existing training programs for minority trainees

(8 K01, basic sciences; 3 K12 positions; 10 R25 positions). ■ Establish 10 Minority Institution/NCI Cancer Center Research, Training, Education,

and Outreach Partnerships.

Improve infrastructure for developing and enhancing programs and for communication about NCI training and career development opportunities. $8.2 M■ Continue developing, refining, and integrating NCI Internet-based information systems.■ Improve communication with professional organizations about NCI training opportunities. ■ Provide supplements to cancer centers to foster communication and outreach to scientists.■ Improve interactions with graduate schools, medical schools, and schools of public health.■ Recruit additional NCI staff to manage new activities.


TOTAL $60.7 M

The National Cancer Institute’s TheNation’s Investment in Cancer Research

is a truly collaborative effort. As in thepast, the document has benefited fromthe insights, perspectives, contributions,commitment, and review of countlesspeople both within NCI and in researchand academic institutions and profession-al organizations throughout the country.

Two NCI offices, the Office of SciencePolicy and the Office of Budget andFinancial Management, played key roles in developing and assembling informationfor this book. In particular, several mem-bers of NCI staff merit special recognitionfor their contributions. Cherie Nichols pro-vided leadership, motivation, insight, andcounsel. Her efforts sparked, guided andsustained the project’s progress from ini-tial plan to final printing. Catherine Law,Anna Levy, Jane Lockmuller, Kate Nagy,and Anne Tatem conceptualized, wrote,and edited the vast majority of the text.Their exceptional skills and perseverancewere essential in the production this doc-ument. We are grateful to Susan Rossi forher scientific input and editing, to CherylParrott for her writing contributions andediting skills, and to Susan Waldrop forher writing contributions. We are alsoindebted to Suzanne Reuben for her excel-lent editing and writing contributions.Finally, we are grateful to John Hartingerand the staff of the Office of Budget andFinancial Management for their fiscalknowledge and guidance.

Extraordinary Opportunity andChallenge ChampionsThis year each Extraordinary Opportunityand Challenge was represented by “cham-pions” - members of NCI staff expert inthese areas of special research investmentwho aided in crafting the vision, plans,progress, and resources for each opportu-nity or challenge. The efforts of thesechampions and countless NCI staff mem-bers who assisted them helped us toarticulate this critical information.

Extraordinary OpportunitiesGenes and the Environment - Dr. Richard

Klausner, Dr. Joseph FraumeniCancer Imaging - Dr. Robert Wittes,

Dr. Ellen FeigalDefining the Signatures of Cancer Cells:

Detection and Diagnosis - Dr. Richard Klausner, Dr. Peter Greenwald

Molecular Targets of Prevention and Treatment - Dr. Richard Klausner, Dr. Robert Wittes

Research on Tobacco and Tobacco-RelatedCancers - Dr. Richard Klausner, Dr. Barbara Rimer

Cancer Communications - Dr. Richard Klausner, Dr. Barbara Rimer

ChallengesInvestigator-Initiated Research -

Dr. Marvin Kalt, Dr. Norka Ruiz BravoCenters, Networks, and Consortia -

Dr. Ellen Feigal, Dr. Brian KimesNational Clinical Trials Program -

Dr. Robert Wittes, Dr. Michaele Christian

Informatics and Information Flow - Mr. James Silva, Ms. MaryAnn Guerra

Studying Emerging Trends in Cancer - Dr. Robert Hiatt, Dr. Brenda Edwards

Training, Education, and Career Development - Dr. Brian Kimes

FY 2001 Editorial BoardThe Nation’s Investment in CancerResearch serves two important functions:it describes NCI’s research portfolio andthe future path we have identified as themost direct route to conquering cancer.With this in mind, we enlisted the help ofseveral NCI staff with expert scientificknowledge, an over-arching perspectiveon the Institute’s activities and goals,and keen understanding of promisingopportunities in cancer research. Theseindividuals, our Editorial Board, helpedshape the content of this book.

Dr. Norka Ruiz Bravo, Ms. JulianneChappell, Dr. Ellen Feigal, Mr. JohnHartinger, Dr. Barry Kramer, Dr. AlfredKnudson, Dr. Edison Liu, Dr. BarbaraRimer, Dr. Margaret Tucker, Mr. Paul Van Nevel.

FY 2001 Bypass Planning CommitteeWe thank the members of our planningcommittee who helped to ensure that thisdocument clearly and accurately describesthe excitement and promise of ourresearch efforts, NCI’s needs and plans,and the vision for the future of ourresearch programs.Dr. Richard KlausnerDirectorDr. Alan RabsonDeputy DirectorDr. Robert WittesDeputy Director, Extramural Science andDirector, Division of Cancer Treatment and DiagnosisDr. Norka Ruiz Bravo*Deputy Director, Division of ExtramuralActivities, National Institute of GeneralMedical Sciences

Dr. Ellen FeigalDeputy Director, Division of CancerTreatment and DiagnosisDr. Joseph FraumeniDirector, Division of Cancer Epidemiologyand GeneticsDr. Paulette GrayDeputy Director, Division of ExtramuralActivitiesDr. Peter GreenwaldDirector, Division of Cancer PreventionMs. MaryAnn GuerraDeputy Director, ManagementDr. Joseph HarfordAssociate Director, Special ProjectsMr. John HartingerAssociate Director, Financial ManagementDr. Marvin KaltDirector, Division of Extramural ActivitiesDr. Alfred KnudsonSpecial Advisor, Division of CancerEpidemiology and GeneticsDr. Edison LiuDirector, Division of Clinical SciencesMs. Cherie NicholsAssistant Director, Science Planning andAssessmentDr. Barbara RimerDirector, Division of Cancer Control andPopulation SciencesDr. Susan Sieber Associate Director, Special ProjectsDr. George Vande WoudeDirector, Division of Basic SciencesMs. Susan WaldropAssistant Director, Program Coordination

Dr. Sherry Mills, ChairExtramural Advisory Board

Dr. Allan Weissman, ChairDr. Margaret TuckerIntramural Advisory Board

Dr. David Livingston, ChairBoard of Scientific Advisors

Dr. Martin Abeloff, Co-chairDr. Bruce Stillman, Co-chairDr. Matthew Scharff, MemberBoard of Scientific Counselors

Ms. Lillouise Rogers, MemberDirector’s Consumer Liaison Group

Dr. J. Michael Bishop, ChairDr. Philip Schein, MemberDr. Phillip Sharp, MemberMs. Ellen Stovall, MemberNational Cancer Advisory Board

* Former Acting Director, Division of Cancer Biology, NCI

Acknowledgments

NIH Publication No. 99-4373 T206October 1999

Additional copies of The Nation’s Investment in Cancer Research: A Budget Proposal for Fiscal Year 2001can be ordered by fax at 301-330-7968, by e-mail at [email protected], or by phone at 1-800-4-CANCER. Or, you may view the document and previous Bypass Budgets online at http://www.nci.nih.gov

FOR ADDITIONAL INFORMATION ON:■ CANCER visit us online at http://cancernet.nci.nih.gov where patients, health professionals, and the public

can find information about the different types of cancer, screening, diagnosis, and state-of-the-art care. Or, call NCI’s Cancer Information Service at 1-800-4-CANCER to speak with an information specialist.

■ CLINICAL TRIALS visit the Physician Data Query (PDQ) data base at http://cancernet.nci.nih.gov or visit our clinical trials resource, cancerTrials, at http://cancertrials.nci.nih.gov, which provides information aboutongoing prevention, detection, diagnosis, and treatment clinical trials – including links to data bases of ongoing studies and general information about clinical trials.

■ CANCER CENTERS call NCI’s Cancer Centers Branch at 301-496-8531 or visit http://www.nci.nih.gov/cancercenters/. For a list of NCI-designated Cancer Centers visithttp://www.nci.nih.gov/cancercenters/centerslist.html

■ GRANTS AND CONTRACTS visit NIH’s Grants and Contracts page at http://www.nih.gov/grants

■ TRAINING, EDUCATION, AND CAREER DEVELOPMENT call NCI’s Cancer Training Branch at 301-496-8580. A new Web site is being developed and will be accessible from NCI’s home page at http://www.nci.nih.gov

■ SURVEILLANCE visit the Surveillance, Epidemiology, and End Results (SEER) Program athttp://www.seer.ims.nci.nih.gov

the nation’s investment in cancer research · the nation’s investment in cancer research, the...

Documents