curing cancer (john marshall, m.d.)

8/7/2019 Curing Cancer (John Marshall, M.D.)

1/29

1

Curing Cancer

John Marshall, MD

Professor of Medicine and Oncology

Georgetown University

Lombardi Comprehensive Cancer Center


2/29

The War on Cancer is DeclaredRichard Nixon, 1971

"I will also ask for an appropriation of an extra$100 million to launch an intensive campaign tofind a cure for cancer, and I will ask later for

whatever additional funds can effectively beused. The time has come in America when thesame kind of concentrated effort that split theatom and took man to the moon should be

turned toward conquering this dread disease.Let us make a total national commitment toachieve this goal."


3/29

NCI Funding 2005-07

The US spent $5.6 billion on cancer research in 2006


4/29

Cancer Research

A Super Fraud? "Everyone should know that most cancer

research is largely a fraud and that themajor cancer research organizations arederelict in their duties to the people whosupport them." - Linus Pauling PhD (Two-

time Nobel Prize winner).


5/29

What went right?

Have cured and conquered some cancers

Leukemia

Lymphoma

Germ Cell cancers

Childhood Cancers

Screening/Early Detection/Prevention

Breast, Colon, Cervix, Skin


6/29

The view from 35,000 feet

Everything looks the same from up here


7/29


8/29

What went wrong?

Adenocarcinomas

Progression free survival

Declaring response rates do not correlatewith survival

Accepting low response rates

Health Care Costs, no sense of value


9/29

How it happened

Patient/Consumer

Physicians, ProvidersHospitals, Services

PharmaHealth Insurance/

Government

$$ $$

$$$$

US Industry

$$ $$


10/2910

Success in the Treatmentof Colorectal Cancer

1980 1985 1990 1995 2000 2005

Therapeutic concepts

Palliative chemotherapy

Adjuvant chemotherapy

Neoadjuvant chemotherapy

Capecitabine

Oxaliplatin

Cetuximab

Bevacizumab

Irinotecan

5-FU

Panitumumab

Targeted therapies

{


11/29


12/2912

15.6

20.3 19.921.3

23.1

28.0

17.6

19.220.7

26.027.0

0

5

10

15

20

25

30

IFLIFL+bevacizum

ab

FOLFO

X/CapeOx+B

ev

FOLFO

X/CapeOx

FOLFIRI

FOLFIRI+bevacizum

ab

mIFL

mIFL+bevacizum

ab

bFOL+bevacizumab

mFOLFOX+bevacizum

ab

CapeOx+bevacizum

ab

First-Line Bevacizumab in MCRC:Overall Survival

aP


13/2913

EGFR: One of Many Signaling Modulesin Cancer Cells

Hanahan, Weinberg, Cell 100:57, 2000


14/2914

Proliferation MetastasisAngiogenesisApoptosisResistance

Shc

PI3-K

RafMEKK-1

MEKMKK-7

JNK

ERK

Ras

mTOR

Grb2

AKT

Sos-1

What is the Role of the Epidermal Growth FactorReceptor (EGFR) in Cancer?

Cell Membrane

EGFR

SignalingProteins

CellResponse

to Signaling


15/2915A. Friedman and N. Perrimon, Cell 128, January 26, 2007

Pathway vs. Network signaling

Network

Chaotic

Pathway

Newtonian


16/2916

Shc

PI3-K

RafMEKK-1

MEKMKK-7

JNK

ERK

Ras

mTOR

Grb2

AKT

Sos-1

Proliferation MetastasisAngiogenesisApoptosisResistance

EGFR

SignalingProteins

CellResponse

to Signaling


17/2917

Shc

PI3-K

RafMEKK-1

MEKMKK-7

JNK

ERK

Ras

mTOR

Grb2

AKT

Sos-1

Which Target?


18/2918

Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center

Sos-1

Ras

MEKK-1

MEK

Shc

PI3-K

Raf

MKK-7

Grb2

AKT

JNK

ERK


19/2919

Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center

Sos-1

Ras

MEKK-1

MEK

Shc

PI3-K

Raf

MKK-7

Grb2

AKT

JNK

ERK

Wheres the target?

The EGF Receptor Interactome

638 Genes


20/2920

Adjuvant therapy for colon cancer fails95% of the time in stage II colon cancer

Quasar Lancet. 2000 May 6;355(9215):1588-96

We are under-treating

We are over-treating


21/2921

NSABP C-08

R

mFF6 q2wk X 6 mo

Bev* q2wk X 1 yr

*5mg/K


22/29


23/2923

pmTOR-immunostaining (Ventana)

Critical: Postsurgical ischemia


24/2924

Inconvenient Truths

Adjuvant therapy fails most of the time. Only a small percentage are cured with treatment

Phase III trials are designed to detect small differences When PFS became acceptable, we decided we were not going to cure

cancer

Clinical trial accrual in the US is at an all time low. We now off shore this to the lowest bidder, most in need?

Cancer treatment adds relatively little to survival If you had to pay for it, would you?

Cancer as a chronic disease is not the same as other chronic diseases The cost of colon cancer therapy now exceeds the cost of dialysis

Many Pipeline drugs- not enough money, not enough patients?


25/29

25

We are in a time of change

We now acknowledge the errors of the past

We have better technology to support the war A new kind of war

We know that success will require work, collaboration andsacrifice

The rewards are unimaginable

Are our hearts in this? Do we have the stomach for it?


26/29

26

A Proposal for New Drug Development inCancer

10 Patient Phase II Trials

MolecularEnrichment

MolecularEnrichment

Repeat


27/29

27

Where we are Where we need to be

Safety and Efficacy Value

Cancers are the same Cancers are different

Defining cancers by site of origin Defining cancers by molecularprofile

Phase III trials with PFS as

endpoint

Phase II trials with response rate as

endpoint

Only watching the tumor Watching the tumor and the hostresponse


28/29

28

US Capitol

Pentagon

The White House

My office


29/29

curing cancer (john marshall, m.d.)

Documents