8 -10 march 2010 molecular cancer therapeutics · adrian senderowicz, astrazeneca, philadelphia,...

Charles Rudin, The Johns Hopkins University,Baltimore, USAAdrian Senderowicz, AstraZeneca,Philadelphia, USALillian Siu, Ontario Cancer Institute,Toronto, CanadaJosep Tabernero, Vall d’Hebron University Hospital,Barcelona, SpainJaap Verweij, Erasmus University Medical Center,Rotterdam, The NetherlandsDan Von Hoff, Translational Genomics Research Institute,Phoenix, USARichard Wahl, The Johns Hopkins PET Center,Baltimore, USADoug Yee, University of Minnesota,Minneapolis, USA

8 -10 March 2010

MolecularCancer Therapeutics

Organisers:S. Gail Eckhardt,University of Colorado Denver, Aurora, USARoy S. Herbst,The University of Texas MD Anderson Cancer Center,Houston, USAManuel Hidalgo,CNIO, Madrid, Spain

SUMMARYDetailed Programme

5

Speaker Abstracts11

Invited Speakers´ Biographies43

List of Invited Speakers, Short Talk Speakers and Organisers

Calendar of CNIO Conferences 2010Previous CNIO Cancer Conferences

67

DETAILED PROGRAMME

Patients

Drugs

Cancer

6

Molecular Cancer TherapeuticsMolecular Cancer TherapeuticsMONDAY 8th

Welcome addressManuel Hidalgo

SESSION I

Emerging new cancer targets and drugs

Chair : Roy S. Herbst

09:15 – 11:00Douglas YeeAlex Adjei

Patricia LoRusso

COFFEE BREAK

11:40 – 12:50Josep Tabernero

Adrian Senderowicz

LUNCH

SESSION IILessons learned from recent successfully

developed new agentsChair : Alex Adjei

14:20 – 16:40Jaap VerweijGary Clark

Eric RowinskyManuel Hidalgo

COFFEE BREAK

17:10 – 18:00

Keynote address Chair : S. Gail Eckhardt

Neal Rosen

TUESDAY 9th

SESSION IIIInnovation in clinical

trials designChair : Josep Tabernero

08:50 – 11:10

Elisabeth Garrett-MayerLillian Siu

Emiliano CalvoLajos Pusztai

GROUP PICTURE AND

COFFEE BREAK

SESSION IVEmerging new

anticancer agents Chair : Lillian Siu

11:40 – 13:25Charles Rudin

Johann de BonoS. Gail Eckhardt

LUNCH

SESSION V

Short talks from selected abstracts

Chair : Elisabeth Garrett-Mayer

15:00 – 17:00

Magdalena B. WozniakCristina Gómez-Abad

Miguel Quintela-FandinoChristopher Heeschen

Magdalena ZajacJordi Rodon

COFFEE BREAK

17:30 – 18:20Keynote address

Chair : Manuel Hidalgo Dan Von Hoff

WEDNESDAY 10th

SESSION VIApplying biomarkers toclinical cancer researchChair : Emiliano Calvo

09:10 – 10:55Richard Wahl

Antonio JimenoRoy S. Herbst

CLOSING REMARKS

Roy S. HerbstS. Gail Eckhardt

Molecular Cancer Therapeutics

7

Molecular Cancer TherapeuticsMONDAY, MARCH 8th

09:00 - 09:15 Welcome address Manuel Hidalgo, CNIO, Madrid, Spain

SESSION IEmerging new cancer targets and drugsChair : Roy S. Herbst

09:15 - 09:50 Douglas Yee, University of Minnesota, Minneapolis, USA “Targeting the insulin-like growth factor receptor as a new cancer therapy”

09:50 - 10:25 Alex Adjei, Roswell Park Cancer Institute, Buffalo, USA “Targeting the Ras/Raf/MEK pathway for cancer therapy”

10:25 - 11:00 Patricia LoRusso, The Barbara Ann Karmanos Cancer Institute, Detroit, USA “cMET as a target for cancer therapeutics”

11:00 - 11:40 Coffee break

11:40 - 12:15 Josep Tabernero, Vall d´Hebron University Hospital, Barcelona, Spain “Inhibitors of the PI3K pathway”

12:15 - 12:50 Adrian Senderowicz, AstraZeneca, Philadelphia, USA “Development of JAK inhibitors for the treatment of human neoplasms”

12:50 - 14:20 Lunch

SESSION IILessons learned from recent successfully developed new agentsChair : Alex Adjei

14:20 - 14:55 Jaap Verweij, Erasmus University Medical Center, Rotterdam, The Netherlands “Clinical development of imatinib mesylate in GIST: Understanding

the target”

14:55 - 15:30 Gary Clark, Array BioPharma, Boulder, USA “Erlotinib: Strategies for a successful clinical development”

15:30 - 16:05 Eric Rowinsky, New York University School of Medicine, New York, USA “Cetuximab in colorectal cancer: Lessons learned about the

development of enrichment biomarkers to maximize the therapeutic index of cancer therapeutics.”

16:05 - 16:40 Manuel Hidalgo, CNIO, Madrid, Spain “Clinical development of mTOR inhibitors in cancer treatment”


17:10 - 18:00 Keynote address Chair : S. Gail Eckhardt Neal Rosen, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, USA “Targeting oncogene addition”

8

Molecular Cancer TherapeuticsMolecular Cancer TherapeuticsTUESDAY, MARCH 9th

SESSION IIIInnovation in clinical trials designChair : Josep Tabernero

08:50 - 09:25 Elisabeth Garrett-Mayer, Medical University of South Carolina, Charleston, USA “Novel trial designs for early phase drug development”

09:25 - 10:00 Lillian Siu, Ontario Cancer Institute, Toronto, Canada “Using phase II trials to fulfill their “Go-No-Go” role”

10:00 - 10:35 Emiliano Calvo, Centro Oncológico Clara Campal, Madrid, Spain “Strategies to combine molecular targeted agents in the clinic”

10:35 - 11:10 Lajos Pusztai, University of Texas MD Anderson Cancer Center, Houston, USA “Clinical trial design to prospectively test molecular markers and patient selection strategies”

11:10 - 11:40 Group picture and coffee break

SESSION IVEmerging new anticancer agentsChair : Lillian Siu

11:40 - 12:15 Charles Rudin, The Johns Hopkins University, Baltimore, USA “Targeting the hedgehog pathway in cancer”

12:15 - 12:50 Johann de Bono, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, UK

“Biomarker driven early anticancer drug development”

12:50 - 13:25 S. Gail Eckhardt, University of Colorado Denver, Aurora, USA “PAK4, a novel anticancer target”

13:25 - 15:00 Lunch

SESSION VShort talks from selected abstracts Chair : Elizabeth Garrett-Mayer

15:00 - 15:20 Short talk: Magdalena B. Wozniak, CNIO, Madrid, Spain “Synergistic effects of histone deacetylase and PI3K inhibitors in cutaneous

T-cell lymphoma”

15:20 - 15:40 Short talk: Cristina Gómez-Abad, CNIO, Madrid, Spain “PIM as a rational target for B-cell lymphomas”

15:40 - 16:00 Short talk: Miguel Quintela-Fandino, CNIO, Madrid, Spain “Individual optimal biologic dose titration of sorafenib based on a

pharmacodynamic test”


9

Molecular Cancer Therapeutics16:00 - 16:20 Short talk: Christopher Heeschen, CNIO, Madrid, Spain “Inhibition of ATR function abrogates in vitro and in vivo tumorigenicity

of human colon cancer cells through depletion of CD133+ tumor-initiating cells”

16:20 - 16:40 Short talk: Magdalena Zajac, CNIO, Madrid, Spain “Hsp70 as a biomarker of response and prognostic marker to Hsp90

inhibitor, 17AAG, in breast tumors”

16:40 - 17:00 Short talk: Jordi Rodon, Vall d´Hebron - Institute of Oncology, Barcelona, Spain “Selecting patients for a phase I trial in the era of targeted therapies”


17:30 - 18:20 Keynote address Chair : Manuel Hidalgo Dan Von Hoff, Translational Genomics Research Institute, Phoenix, USA “Sequencing for 6000!”

WEDNESDAY, MARCH 10th

SESSION VIApplying biomarkers to clinical cancer researchChair : Emiliano Calvo

09:10 - 09:45 Richard Wahl, Johns Hopkins PET Center University, Baltimore, USA “Functional imaging in drug development”

09:45 - 10:20 Antonio Jimeno, The University of Colorado at Denver, Aurora, USA “Pharmacodynamic testing: new directions”

10:20 - 10:55 Roy S. Herbst, The University of Texas MD Anderson Cancer Center, Houston, USA “Phase II randomized study of biomarker-directed treatment for non-small cell lung cancer (NSCLC): The BATTLE (Biomarker-Integrated

Approaches of Targeted Therapy for Lung Cancer Elimination) clinical trial program”

10:55 Closing remarks Roy S. Herbst, The University of Texas MD Anderson Cancer Center, Houston, USA S. Gail Eckhardt, University of Colorado Denver, Aurora, USA

Note: Talks: 25 minutes / Short talks: 15 minutes / Keynote: 40 minutes / Discussions: 10 minutes after each talk / 5 minutes after each short talk / 10 minutes after each keynote address

SPEAKERABSTRACTS

Patients

Drugs

Cancer

12

Molecular Cancer TherapeuticsMolecular Cancer Therapeutics

The growth, survival, and development of normal cells is influenced by endocrine, autocrine, and paracrine factors. One of the most studied pathways is the insulin-like growth factor (IGF) system. While IGF signaling is not essential for life, it is required for many tissues to fully develop. Cancer cell proliferation, survival, and metastasis are stimulated by the activation of this pathway. The IGF system is composed of multiple components; three ligands (insulin, IGF-I, and IGF-II), four receptors (type I IGF receptor – IGF1R, insulin receptor – InsR, hybrid receptors, and the type II IGF receptor (IGF2R), and six high affinity extracellular binding proteins. Once activated, the IGF family of transmembrane tyrosine kinase receptors can signal to multiple downstream cellular networks. Most anti-IGF drugs target IGF1R. Monoclonal antibodies and tyrosine kinase inhibitors have shown some promise in early clinical trials, but there have also been some setbacks. Antibodies effectively inhibit signaling by downregulating the IGF1R, but have less effect on InsR. In contrast, tyrosine kinase inhibitors disrupt the biochemical function of both receptors. To address the relevance of insulin receptor signaling to cancer biology, we created cells (MDA-435/LCC6 and T47D) with shRNA downregulation of InsR. These cells have reduced tumor growth and metastasis, highlighting the importance of InsR to cancer cell behavior. In addition to identifying relevant receptor targets, we have also demonstrated that the insulin receptor substrate (IRS) proteins link IGF/insulin signaling to specific cancer phenotypes. Recently, we examined gene expression profiling downstream of IGF1R activation in T47D cells and have found that the gene expression profile patterns are different between IRS-1 and -2. Furthermore, IRS-derived gene expression profiles identify tumors with more aggressive biological behavior. Disrupting the signaling pathway of these receptors shows promise as cancer therapy and additional modeling in preclinical systems should guide the development of appropriate clinical applications.

Targeting the insulin-like growth factor receptor as a new cancer therapy

DOUGLAS YEE, Annabell S. Oh, Marc Becker, Kelly LaPara, Xihong Zhang, Dedra H. Fagan and Hua Zhang. Masonic Cancer Center, Departments of Medicine and Pharmacology, University of Minnesota, Minneapolis, USA

Chair: Roy S. HerbstEmerging new cancer targets and drugs

SESSION I


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Targeting the Ras/Raf/MEK pathway for cancer therapy

ALEX ADJEIRoswell Park Cancer Institute, Buffalo, USA

Anchorage-independent growth, a hallmark of neoplasia, describes the ability of cells to proliferate in the absence of substratum adhesion. Studies into the phenomenon revealed mitogen-activated protein kinase (MAPK) pathway as a ma-jor connector between extra- and intracellular stimuli, such as growth factors, cytokines and oncogenes, and cellular respon-ses related to adhesion, motility, proliferation and malignant transformation. Ras is a small GTPase protein that transmits activating signals from growth factors, cytokines and oncoge-nes, to Raf and then to MAPK kinase (MEK). MEK then phos-posphorylates and activates the extracellular signal-regulated kinase (ERK, also known as MAPK). Ras, Raf and MEK are the main targets in the pathway, which is the most frequently mu-tated oncogenic kinase pathway in human cancer. The Ras/Raf/MEK pathway is therefore attractive as a cancer target. Appro-aches to target mutant ras continue to evolve, with no data on a truly viable drug candidate. The MEK inhibitors have been evaluated in the clinic since 2000, over 7 agents are now in the clinic; RDEA 119, XL518, TAK-733, ARRY-162, AZD8330 and GSK 1120212 among others, are in phase I trials. AZD6244 is in phase II testing and phase I combinations Challenges to their development will be discussed. Exciting new data on the efficacy of raf kinase inhibitors in B-raf mutant melanoma with a focus on PLX-4032, which putatively specifically targets mu-tant B-raf will also be discussed. This agent will be compared to the multi-targeted agents that inhibit wild-type raf as well as other angiogenic kinases (XL-218, RAF-265.


SESSION I

14


c-MET signaling is implicated in a wide variety of human malignancies. Inappropriate signaling occurs in virtually all types of solid tumors and can participate in all stages of cancer development. Extensive evidence that c-MET signaling is involved in the progression and spread of several cancers and an enhanced understanding of its molecular importance have made c-MET and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), major targets in cancer drug development and have accelerated the development of a variety of potentially clinically useful c-MET pathway antagonists. The 3 main approaches of pathway selective anti-cancer drug development have included: antagonism of ligand/receptor interaction, inhibition of the tyrosine kinase catalytic activity, and blockade of the receptor/effector interaction. Particularly, with regards to tyrosine kinase inhibition, multi-targeted therapies have been under investigation in the clinic that have demonstrated promise. Several c-MET antagonists are now under clinical investigation. Preliminary results of several of these agents, both monoclonal antibodies and small inhibitors, have been encouraging and will be discussed in this presentation.

cMET as a target for cancer therapeutics

PATRICIA LORUSSO Karmanos Cancer Institute, Detroit, USA


SESSION I


15


Inhibitors of the PI3K pathway

JOSEP TABERNEROVall d’Hebron University Hospital, Barcelona, Spain

The phosphatidylinositol 3-kinase (PI3K) signalling pathway is integral to diverse cellular functions, including cellular proliferation, differentiation and survival. The ‘phosphate and tensin homologue deleted from chromosome 10’ (PTEN) tumour suppressor gene plays a critical role as a negative regulator of this pathway. An array of genetic mutations and amplifications has been described affecting key components of this pathway, with implications not only for tumorigenesis but also for resistance to some classic cytotoxics and targeted agents. Emerging pre-clinical research has significantly advanced our understanding of the PI3K pathway and its complex machinations and interactions. This knowledge has enabled the evolution of rationally designed drugs targeting elements of this pathway. It is important that the development of suitable biomarkers continues in parallel to optimize use of these agents. A new generation of PI3K inhibitors are now entering early clinical trials, with much anticipation that they will add to the growing armamentarium of targeted cancer therapeutics.


SESSION I

16


JAK/STAT signalling pathway is involved in a variety of proliferative and cancer-related processes including cell-cycle progression, apoptosis, angiogenesis, invasion, metastasis and evasion of the immune system. Cytokine and/or growth factor binding to cell-surface receptors activates JAK by autophosphorylation, leading to Stat activation and nuclear translocation. Once in the nucleus, the STATs bind DNA and cooperate with other transcription factors to regulate expression of a number of genes including genes encoding apoptosis inhibitors (eg Bcl-XL) and cell cycle regulators (eg Cyclin D1/D2). Constitutive activation of the STAT family, in particular STAT3 and STAT5, has been detected in a wide range of malignancies and hyperproliferative disorders. AZD1480 is a novel small molecule that potently inhibits jak2 (IC50: < 1nM). AZD1480 inhibits the growth of multiple solid tumor xenografts harboring persistent Stat3 activity, including DU145 (prostate), MDA-MB-468 (breast) and MDAH2774 (ovarian) (Hedvat et al: Cancer Cell 16, 487-497, 2009). Pharmacodynamic analysis of Stat3 phosphorylation demonstrated significant inhibition of pStat3. Moreover, reduction of Stat3 expression with shRNA in MDA-MB-468 xenografts significantly inhibited tumor growth. However, introduction of a constitutively active Stat3C mutant into 786-0 xenografts caused these tumors to become resistant to AZD1480 treatment (Hedvat et al). These findings further support the conclusion that tumor growth inhibition observed upon treatment with AZD1480 is dependent at least in part on inhibition of Stat3 signaling (Hedvat et al). The first Phase I trial of AZD1480 started in May 2009 and is recruiting myelofibrosis patients. These data support the development of Jak inhibitors for treatment of neoplastic diseases including solid tumors.

Development of JAK inhibitors for the treatment of human neoplasms

ADRIAN SENDEROWICZand Dennis Huszar, AstraZeneca, Philadelphia, USA


SESSION II


17


Imatinib mesylate is a highly selective inhibitor of the protein tyrosine kinase family comprising Abl, PDGF, and the product of the c-Kit proto-oncogen (KIT). The KIT protein is the receptor tyrosine kinase (RTK) for the ligand stem cell factor (SCF). It is found on a variety of normal and tumor cells. Deregulation of SCF receptor signaling is involved in a variety of human cancers. Particularly Gastro-Iintestinal Stromal Tumors (GIST) are characterized by presence of activating mutations of KIT. In models these mutations appeared extremely sensitive to Imatinib, while the wild-type KIT was not. Indeed in GIST Imatinib was shown to be very active, with activity being partly linked to presence or absence of an activating mutation of the receptor. Patients with tumors harboring a mutation of exon 11 were are most sensitive, those with mutations in exon 9 or harboring wild-type c-Kit where much less sensitive, while as predicted from the pre-clinical studies patients with a mutation of exon 17 did not respond. Studies in tumor types over expressing wild-type c-KIT did not show any antitumor activity. This confirms that presence of one of the molecular targets of Imatinib itself is not enough to expect anti-tumor effect, and that specific aberrations are required. Assessing the functionality of the target prior to embarking into clinical studies thus is relevant. Two randomized phase III studies have subsequently assessed the issue of a possible dose-response relationship, randomizing patients to either 400 mg or 800 mg daily. The higher dose leads to a significantly longer progression free interval. Also patients crossing over after progression of disease from the standard dose to the higher dose seem to be able to benefit again of the dose increase. This indicates that resistance to the standard dose may partly be pharmacokinetic. Other reasons for resistance seem to be biological and consist of increasing appearance of drug-insensitive new mutations. Imatinib presents a unique example of effective targeted treatment and may serve a role model for developing other targeting agents.

Clinical development of imatinib mesylate in GIST: Understanding the target

JAAP VERWEIJ Erasmus University Medical Center, Rotterdam, The Netherlands

Chair: Alex AdjeiLessons learned from recent successfully developed new agents

SESSION II

18


Erlotinib (Tarceva®) is a small molecular inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. It was approved in the United States in 2004 as monotherapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen, and in 2005 in combination with gemcitabine for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer. The development path from first clinical trial to registration required 7 years, but involved some unusual management decisions and interesting discussions with regulatory authorities. The initial studies were conducted in healthy volunteers who experienced a high frequency of rash, which nearly killed the development program. Initial studies in cancer patients required EGFR positivity, but this requirement was dropped in subsequent studies. Tumor responses were infrequent, but prolonged stable disease was often observed, suggesting that overall survival rather than RECIST criteria was a more appropriate clinical endpoint for pivotal studies. While accrual to Phase III studies in patients with NSCLC was ongoing, activating EGFR mutations were identified by other investigators which led to a series of strategic decisions regarding the clinical development plan. A pivotal Phase III study in patients with pancreatic study was initiated before the results of a Phase Ib combination study were available, leading to an unorthodox Phase I/III approach for evaluating the combination of erlotinib and gemcitabine. At the completion of the pivotal Phase III trials, questions about patient selection remained unanswered, and controversies continue regarding which patients should receive this treatment. As a consequence, the approved indication for patients with pancreatic cancer is different in the EU and in the US. Although lessons learned from this drug development experience may not generalize to other compounds, they can be instructive from a historical perspective.

Erlotinib: Strategies for a successful clinical development

GARY M. CLARKArray BioPharma Inc., Boulder, USA


SESSION II


19


Cetuximab in colorectal cancer: Lessons learned about the development of enrichment biomarkers to maximize the therapeutic index of cancer therapeutics

ERIC ROWINSKYImClone Systems, New York, USA


The development of the epidermal growth factor receptor (EGFR) blocking chimeric monoclonal antibody cetuximab for colorectal cancer (CRC) is a case study illustrating the scientific, logistical, and regulatory challenges involved with the development of biomarkers to enrich clinical studies with patients who will derive maximal clinical benefit. Enrichment biomarkers were incorporated into clinical development of cetuximab from its earliest trials as it was felt that only patients whose tumors expressed the putative antibody target - EGFR - would benefit. From the beginning, EGFR expression, as assessed by immunohistochemistry (IHC), was required for study eligibility. This requirement was adopted empirically and no foundational studies that assessed the activity of cetuximab as a function of EGFR immunostaining were performed prior to the incorporation of this eligibility requirement into pivotal studies. Because the pivotal studies provided proof that cetuximab conferred clinical benefit, the requirement for positive EGFR immunostaining was adopted into labeling by the FDA and EMEA. Over the next several years, the pitfalls of EGFR IHC became apparent, and more importantly, it appeared that patients whose cancers lacked EGFR immunostaining had similar responses to cetuximab compared to patients whose tumors had strong EGFR immunostaining; however, such patients had difficulty receiving cetuximab based on previous labeling. These events illustrate the need to truly understand biomarkers that are to serve as a foundation for patient enrichment. On the other hand, K-ras, was never thought to represent a biomarker for cetuximab in its early development, also illustrating the need for unbiased assessments of a full range of biomarkers. The first reports that K-ras mutation status related to cetuximab responsiveness were from retrospective analyses of small phase 2 studies, but despite the limitations of study size, the results were robust. Retrospective analyses of K-ras mutational status from pivotal studies of cetuximab in early and advanced disease showed a similar robustness of K-ras mutational status primarily being a predictive biomarker for cetuximab responsiveness. Similar

SESSION II

20

Molecular Cancer TherapeuticsMolecular Cancer TherapeuticsChair: Alex AdjeiLessons learned from recent successfully developed new agents

findings were confirmed with panitumumab. With regard to cetuximab, the CHMP/EMEA approved it for patients whose tumors were K-ras wild-type. The FDA, concerned about the lack of standardization of K-ras testing and the retrospective analysis (i.e. “data mining”) took a different approach in that the revised label detailed the lack of a therapeutic benefit for patients whose tumors were K-ras mutant. This revised labeling occurred almost 2 years after presentations at major medical meetings. However, not all CRC atients with K-ras wild-type cancers derive benefit from cetuximab and recent retrospective analyses of large studies indicate that various other biomarkers may be used to further enrich studies for patients who are most likely to benefit, thereby sparing others from the toxicity and costs of receiving inappropriate therapies. This case study illustrates the need to incorporate unbiased biomarker assessments in early clinical trials, so that they could be prospectively incorporated into pivotal registration studies.

SESSION II


21


Clinical development of mTOR inhibitors in cancer treatment

MANUEL HIDALGOCNIO, Madrid, Spain

The first clinical trials with mTOR inhibitors for cancer treatment commended in the late 90s with the initial phase I studies with temsirolimus. At that time, these drugs had been approved as immunosuppressors in transplant medicine and much of the debate was to develop doses and schedules that ameliorated the immunosupresing activity of the agent. In paralleled, preclinical studies showed that these agents were more effective in tumor with heightened activation of the PI3K-Akt pathway and that the agent also had antiangiogenesis properties. The development of temsirolimus focused in RCC not so much because the antiagiogenesis activity of the drug but because there were objective response in the phase I trials. The selection of the proper scheduled was based on tolerability and efficacy and the dose was selected in a randomized phase II trial comparing three different dose levels. The lower dose of 25 mg per week was selected and eventually approved for treatment of patients with RCC. The agent was also approved, at a different dose and schedule, to treat patients with MCL that have activation of the cyclin D1. Despite the preclinical rationale suggesting that these agents may be effective in cancer with activation of the PI3K pathway, so far there are no clinical data to support that notion The development of subsequent agents such as everolimus and sirolimus utilized a biomarker driven approach to select dose and schedule of administration. In retrospect it is not clear which of these approaches is better and leads to more effective and better tolerated doses. Likewise, disease oriented studies followed the ¨see a response do a phase II¨ rule more that any biomarker strategy. In summary, the clinical development of mTOR inhibitors illustrates the struggles in new anticancer drug development and will be used to discuss these topics.


SESSION II

22


Novel trial designs for early phase drug development

ELIZABETH GARRETT-MAYER Hollings Cancer Center, Medical University of South Carolina, Charleston, USA

In the past decade, the new agents in development for treating cancer have changed in nature. Early phase drug development had focused on identifying the maximum dose that could be safely given to patients, assuming the highest dose would be most efficacious. Now, many targeted agents have low or no toxicity (in preclinical settings), and a more relevant question is “what is the optimal biologic dose?” There is no guarantee that the relationship between dose and efficacy is monotonic, suggesting that an overdose might not harm the patient, but also may not cure the cancer. In the past several decades, early phase clinical trial design methodology has changed, where Phase I studies have been developed to address questions of both toxicity and efficacy and Phase 0 studies have recently been introduced to provide proof of principle and to help gather information for planning a phase I trial.

Chair: Josep TaberneroInnovation in clinical trials design

SESSION III


23

Molecular Cancer TherapeuticsChair: Josep TaberneroInnovation in clinical trials design

SESSION III

Phase II trials represent a critical step in drug development. They are defined by the FDA “to evaluate the effectiveness of a drug for a particular tumor type and to further determine the common short-term side effects associated with the drug”. The most important function of a phase II trial is to make the “go-no-go” decision – to efficiently screen out inactive drugs while moving promising ones onward for definitive phase III evaluation. A false positive phase II trial will result in an inactive drug entering phase III testing, which is the most expensive phase of drug development. A false negative phase II trial has an even more detrimental consequence of prematurely abandoning the development of a useful drug, which is clearly unacceptable in the era when only 5-8% of oncological compounds being developed in clinical trials eventually reach the market. Ongoing debate exists as to how best to conduct phase II trials to fulfill its screening role. Proponents of single-arm versus randomized phase II trials each support their positions based on various factors. The selection of subjects for phase II trials has also been under much controversy in the molecularly targeted era. The merit of enrichment in early phase clinical trials is uncertain, some investigators strongly believe that this approach will expedite drug development, while others fear that it is too restrictive to limit without sufficient scientific justification.

Using phase II trials to fulfill their “Go-No-Go” role

LILLIAN SIU Ontario Cancer Institute, Toronto, Canada

24

Molecular Cancer TherapeuticsMolecular Cancer TherapeuticsChair: Josep TaberneroInnovation in clinical trials design

Strategies to combine molecular targeted agents in the clinicIn recent years the traditional treatment spectrum of tumors – cytotoxic chemotherapy or radiotherapy – has been extended with rationally designed target-based anticancer drugs. For some tumors, clinical responses have been observed but for numerous others no satisfactory approach has been established. The rapid emergence of hundreds of these new smart agents that modulate an ever-growing list of cancer-specific molecular targets offers tremendous hope for cancer patients. However, evaluating targeted agents individually, in combination with standard treatments, and in combination with other targeted agents presents significant development challenges. Because the number of possible drug combinations is essentially limitless, a strategy for determining the most promising combinations and prioritizing their evaluation is crucial. Here, I will consider the fundamental elements of a development strategy for targeted-agent combinations. Issues that pose challenges to the rational evaluation of such combinations will be described, and possible approaches to overcoming these challenges will be discussed.

EMILIANO CALVO Centro Oncológico Clara Campal, Madrid, Spain

SESSION III


25

Molecular Cancer TherapeuticsChair: Josep TaberneroInnovation in clinical trials design

It is common to employ gene expression profiling as a predictive marker discovery tool in Phase II clinical trials. However, there are several reasons why this supervised approach to predictor discovery may not yield reliable predictors. A simple comparison of transcriptional profiles of breast cancers that respond to chemotherapy in general (or any given drug in particular) with those that did not will reveal many differentially expressed genes. However, most of these genes will reflect the gene expression differences of clinical phenotypic differences between the 2 response groups. Chemotherapy responses are more frequent in high grade, ER-negative cancers compared to low grade and ER-positive tumors, the resulting pharmacogenomic response predictors often represent a predictor of clinical phenotype and may provide only modest added predictive value. The often small gene expression differences that may distinguish responders and non-responders to a given drug in treatment-specific manner are easily masked by the large-scale differences due to any phenotypic imbalance between the response groups. The often small sample size of these discovery studies precludes meaningful adjustment for these confounders. An alternative approach to marker discovery and validation relies on defining candidate predictors based the known mechanism of action of a drug or using results from pre-clinical models and test these prospectively in a clinical trial. Ccandidate predictive marker testing, as opposed to discovery, may be more efficient in Phase II clinical trials. Conceptually, testing a response predictor in a prospective clinical trial is not different from testing a candidate drug in a therapeutic study. We will describe the design and implementation of a parallel, multi-arm, 2-step, Phase II design to rapidly assess the positive predictive values of several different putative predictive markers for various biologically targeted drugs.

Clinical trial design to prospectively test molecular markers and patient selection strategies

LAJOS PUSZTAI The University of Texas MD Anderson Cancer Center, Houston, USA

SESSION III

26


Targeting the Hedgehog pathway in cancerThe Hedgehog signaling pathway is a central developmental regulator controlling cell fate decisions in embryogenesis. Aberrant activity of this pathway may contribute to cancer in multiple ways. In a small subset of cancers, mutations in key components of the Hedgehog pathway appear to be direct contributors to malignant transformation. In these cancers, notably basal cell skin cancer and medulloblastoma, targeted pathway inhibition is associated with remarkable cytotoxic responses. In a larger subset of cancers, Hedgehog signaling may contribute to cancer growth by at least two alternative (but not mutually exclusive) mechanisms. First, the Hedgehog pathway has been implicated in the maintenance, differentiation, and distribution of highly clonogenic cancer progenitors (“tumor stem cells”). Second, Hedgehog signaling activated through a paracrine mechanism by cancer cells on surrounding stromal cells appears to result in stromal changes promoting tumor growth.The pace of translation of research on the Hedgehog signaling pathway has been remarkable. Many of the key components of this pathway in mammalian cells were identified in the mid- 1990s, the first cancer-associated pathway mutation was reported in 1996, and first-generation, non-clinical pharmacologic inhibitors were defined in 2000. Over the past few years, several potent and orally bioavailable targeted inhibitors of Hedgehog signaling have entered phase I clinical testing. Initial data from the first of these phase I trials, using the Hedgehog inhibitor GDC-0449, includes remarkable activity in patients with advanced and metastatic basal cell skin cancer and medulloblastoma, confirming proof of principal for this therapeutic target and this class of agents. Multiple other phase I clinical trials are ongoing or recently completed, and disease-specific phase II trials (single agent studies in medulloblastoma and basal cell carcinoma, and combination studies in other solid tumors) have been initiated.

CHARLES RUDIN The Johns Hopkins University, Baltimore, USA


27


The development of novel molecularly targeted cancer therapeutics remains slow and expensive with many late stage failures. There is thus an urgent need to accelerate drug development by improving early clinical studies through intelligent trial design and incorporating predictive, pharmacokinetic, pharmacodynamic, pharmacogenomic and intermediate endpoint biomarkers. We discuss the current approaches being employed and propose strategies that will potentially maximize benefit to patients and increase the regulatory approvals of novel anticancer drugs.

Biomarker driven early anticancer drug development

JOHANN DE BONO Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton, UK

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PAK4, a novel anticancer target

The p21-activated kinases (PAKs) are a family of serine / threonine kinase signaling molecules that are divided into two subgroups, the GTPase-dependent (PAK1-3) and GTPase-independent (PAK4-6) PAKs. Overexpression has been documented in multiple cancer types including breast, ovarian, colorectal, thyroid, and pancreatic. PAK4 activity is independent of GTPase binding and has been shown to be involved in cell motility, apoptosis, and transformation and is highly expressed in the prostate, colon, and testis. In the Rat1 and NIH 3T3 fibroblast cell lines, transfection with a constitutively active PAK4 resulted in cellular morphology similar to that of transformation, including anchorage-independent growth in soft agar. An investigation into PAK4 expression in human cancer cell lines showed mRNA over-expression in all cell lines tested, including colon cancer cell lines: HT-29, HCC-2998, HCT116, SW620, COLO-205, HCT-15, KM-12 and UO-31, while PAK4 gene amplification was observed in Panc-1, OVCAR-3, and BxPC-3 cell lines. Based upon these data, the PAKs appear to be a promising target for cancer therapy and one such agent in development is PF-3758309, a potent ATP-competitive PAK inhibitor. Concurrent with early clinical development, our lab has been working on developing predictive biomarkers for colorectal cancer (CRC) that can potentially be applied at the end of phase I, in expanded cohorts of patients. Interestingly, across a panel of 30 CRC cell lines, gene array analysis revealed an increase in vimentin and ZEB1 and a decrease in E-cadherin in the sensitive CRC cell lines, indicating that cells with a mesenchymal phentype may be more sensitive to the agent. These and other studies are being expanded with the intent of developing individualized single-agent and combination strategies for PF-3758309 in CRC.

S. GAIL ECKHARDTUniversity of Colorado Denver, Aurora, USA


29


Vorinostat (SAHA), an orally administered inhibitor of class I and II histone deacetylases, has been approved by FDA for the treatment of refractory cutaneous T-cell lymphoma (CTCL). However, due to low response rates (30%), new combination therapies are sought to improve its effect and minimize the toxicity in CTCL. Herein, the molecular effects induced by vorinostat treatment were investigated by analyzing gene expression, cell cycle, apoptosis and signaling pathways. Subsequently, based on the gene expression profile (GEP) of vorinostat, PI3K, PIM and HSP90 inhibitors were evaluated as potential combination agents in the treatment of CTCL. The genes significantly up- or down-regulated by vorinostat over different time periods (2-fold change, FDR corrected p-value<0.05) were selected using short-time series expression miner (STEM). Synergistic effects were evaluated using the method of Chou and Talalay. The functional analysis of gene expression data suggested that vorinostat modifies signaling of T cell receptor (TCR). The phosphorylation studies of ZAP70 (Tyr319, Tyr493) and its downstream target AKT (Ser473) revealed that this HDACi inhibits phosphorylation of these kinases. Furthermore, combined concomitant administration of vorinostat and PI3K inhibitors (LY249002 and new ETP-45658) resulted in synergism and could be potentially efficacious for the treatment of CTCL. In addition, vorinostat and PIM inhibitors showed an additive effect while the use of vorinostat and HSP90 inhibitor (17-AAG) produced antagonistic reaction. In summary, these results demonstrate the potential targets of vorinostat, underlining the importance of TCR signaling inhibition following vorinostat treatment and support the combined use of HDAC and PI3K inihibitors for the treatment of cutaneous T-cell lymphoma.

Synergistic effects of histone deacetylase and PI3K inhibitors in cutaneous T-cell lymphoma

MAGDALENA B. WOZNIAK1, Raquel Villuendas1, James R. Bischoff 2, Carmen Blanco Aparicio2, Juan F. Martínez Leal2, Paloma de La Cueva1, Mª Elena Rodriguez1, Beatriz Herreros1, Daniel Martin-Perez1, Pablo L Ortiz-Romero3 and Miguel Ángel Piris1

1Molecular Pathology Programme, Spanish National Cancer Research Centre, Madrid, Spain; 2Experimental Therapeutics Programme, National Cancer Research Centre, Madrid, Spain; 3Dermatology Department, Hospital 12 de Octubre, Madrid, Spain

SHORTTALK

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Molecular Cancer TherapeuticsMolecular Cancer TherapeuticsSHORTTALK

PIM as a rational target for B-cell lymphomasThe Pim kinases are a family of serine/threonine kinases composed by three members: Pim1, Pim2 and Pim3, involved in the phosphorylation and regulation of several proteins that are essential for cell cycle progression, metabolism or apoptosis (BAD, p21, p27KIP, AKT and cMyc, among them). Overexpression, translocation or amplification of Pim family have been described in many human cancers, including B-cell Non Hodgkin’s Lymphoma, Multiple Myeloma and Prostate cancer. In addition, 50% of patients diagnosed with diffuse large B-cell Lymphoma present somatic mutations in Pim1. Despite of its important role in cancer progression, very few chemical inhibitors have been described in the literature, being effective all of them in the high micromolar range. PURPOSE: Validating PIM as a rational therapeutic target in B-cell lymphoma, developing tools for patient stratification and pharmacodynamic studies on PIM inhibition. MATERIAL AND METHODS: Gene expression profiling and Copy Number data were obtained from a series of 94 B-cell Non-Hodgkin Lymphoma patients (DLBCL, FL, MALT, MCL and NMZL). The effect of Pim inhibition was checked on cell lines by using a novel specific inhibitor for the Pim family (ETP-39010). Newly produced antibodies and RT-PCR primers and protocols were standarized. RESULTS: Gene expression data revealed high Pim isoforms expression in a subset of patients with Mantle cell lymphoma (MCL), and Diffuse Large B-cell lymphoma (DLBLC)-ABC type. CGH analysis focused on chromosomal regions containing Pim family and its main regulatory upstream pathway (JAK/STAT) was performed. Heterozygous gains of Pim1 (6p21.2) and Pim3 (22q13.33) were identified in 13.6% of DLBCL patients and in 4.2% of MCL. Alterations in JAK/STAT pathway were also detected in 59.1% of DLBCL patients, and 37.5% of MCL patients presented any alteration in JAK/STAT pathway, being frequent losses of JAK2 chromosomal

CRISTINA GÓMEZ-ABAD1, Helena Pisonero1, Juan F Leal2, Giovanna Roncador3, José A. Martínez-Climent4, Margarita Sánchez-Beato1, Carmen Blanco-Aparicio2, James Robert Bischoff 5 and Miguel Ángel Piris1

1 Lymphoma’s Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; 2Experimental TherapeuticsProgramme, Assay Development Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; 3 Monoclonal Antibodies Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO),Madrid, Spain; 4Oncology Division, CIMAFoundation for Applied Medical Research, Pamplona, Spain; 5High Throughput Screening Section, Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain


31

Molecular Cancer TherapeuticsSHORTTALK

region. Analysis of additional pathways involved in the up-stream regulation of Pim family disclosed heterozygous gains of PIK3C3 in 40.9% of DLBCL patients, and gains of PIK3CA in 45.9% of MCL patients. Lymphoma cell lines (15) derived from both MCL and ABC-DLBLC subtype, have been analyzed by qRT-PCR and Western-blot, showing variable expression levels of Pim1, Pim2 and Pim3. IC50 obtained for the ETP-39010 compound is in the low micromolar range for the MCL (0.7-8.7 micromolar) and DLBCL-ABC (0.8-10.3 micromolar) cell lines. Since Pim kinase family phosphorilate multiple sites of Bad and AKT, we have checked the inhibition of its phosphorilation as molecular biomarkers for the ETP-39010 effect. Our data show an inhibition of at least 20% of pBad (S112) and almost a complete inhibition of pAKT (S473) 4h after treatment. In addition, cell cycle arrest at G1 and induction of apoptosis were observed 24h after the treatment. CONCLUSION: Pim family genes are a rational therapeutic target in MCL and DLBCL-ABC lymphoma subtypes. Stratification and pharmacodynamic markers have been developed for PIM inhibition using a novel specific inhibitor compound ETP-39010.

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Individual optimal biologic dose titration of sorafenib based on a pharmacodynamic testBackground: large interindividual differences in terms of toxicity and efficacy are observed among patients receiving the standard dose of sorafenib. We developed a test that measures dynamically the degree of inhibition that sorafenib causes in the signal transduction capacity of RAF (RAF-STC), based on an intracellular phosphor-flow platform, assessing the degree of phosphorylation of MEK in stimulated minus basal conditions. Quantitation of the inhibition can be performed directly in a fresh peripheral blood samples. The degree of inhibition achieved in a small cohort of patients receiving sorafenib showed up to 10-fold interindividual variation and was found to be correlated with the TTP. We implemented this test as a tool in order to titrate sorafenib dose individually to the maximum RAF-STC inhibition in patients with neuroendocrine carcinomas. Methods: patients with incurable neuroendocrine tumor and documented PD within 6 months of registration were treated in a run-in phase with a starting dose of 200 mg/bid of sorafenib plus fixed 50 mg/day of cyclophosphamide. Baseline RAF-STC was assessed and then repeated every 14 days. Sorafenib was escalated in 200 mg/bid steps every 14 days until any of the following was achieved: a) 90% inhibition of RAF-STC; b) a maximum dose of 800 mg/bid or c) inacceptable toxicity. After determining the individual dose, patients started cycle 1. Results: 18 patients have been recruited. Starting sorafenib dose ranged from 200 mg q 48 hours to 800mg/bid; maximum STC inhibition ranged from 0 to 100%. An adaptation of RAF STC to sorafenib was observed over time. Toxicity was generally mild and manageable. Among 13 evaluable patients, disease control rate was 85% and median TTP and PFS were 329 and 247 days. Conclusion: this approach appears feasible / safe. Large interpatient differences are observed both in OBD and RAF-STC. Disease control rate is promising.

MIGUEL QUINTELA-FANDINO, Ashley Young, Sheila Webster, Jennifer Petronis, Grewal Mandeep, Anastassios Stathis, Gordon Duncan, Lisa Wang, Malcom J. Moore, Monika Krzyzanowska, Tak W. Mak andLillian L. Siu Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Canada


33


Checkpoint abrogation emerges as a promising approach for selectively killing cancer cells while sparing normal cells. Importantly, its particular impact on the tumor-initiating and chemotherapy-resistant cancer stem cell subpopulation has not yet been systematically investigated. We show here that inhibition of phosphoinositide 3-kinase-related kinase (PIK) proteins by caffeine depleted the CD133+ cell fraction of human colon cancer cell lines and xenograft-derived primary colon cancer cells in a time- and dose-dependent manner. In vitro clonogenicity and in vivo tumorigenicity were drastically reduced in the remaining cell population. The depletion of CD133+ cells was mediated through extrinsic apoptosis of the cycling CD133+ fraction and subsequent recruitment of the quiescent CD133+ fraction. Models using somatic cell gene targeting and RNA interference demonstrated that these effects were mediated by the PIK kinase ATR: inhibition of ATR function depleted the CD133+ cell fraction along with a strongly decreased tumorigenicity of the remaining cells. Most importantly, ATR inhibition virtually abrogated chemo-resistance of CD133+ cells. Taken together, our study illustrates a novel targeted approach to eliminate the tumor-initiating cell fraction in colon cancer and provides a strong rationale for the development of specific ATR-inhibitors.

Inhibition of ATR function abrogates in vitro and in vivo tumorigenicity of human colon cancer cells through depletion of CD133+ tumor-initiating cells

CHRISTOPHER HEESCHEN2, Eike Gallmeier1, Patrick C. Hermann2, Maria-Theresa Mueller2, Juan G. Machado2, Andreas Ziesch1, Enrico N. De Toni1, Andreas Palagyi1, Christian Eisen3, Joachim W. Ellwart4, José Rivera2, Belen Rubio-Viqueira2, Manuel Hidalgo2, Fred Bunz5, Burkhard Göke1

1 Department of Medicine II, Campus Grosshadern, Ludwig-Maximilian-University of Munich, Munich, Germany2 Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain3 Division of Stem Cells and Cancer, German Cancer Research Centre (DKFZ), Heidelberg, Germany4 Institute of Molecular Immunology, Helmholtz Centre, Munich, Germany 5 Department of Radiation Oncology at Johns Hopkins University, Baltimore, USA

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Within the field of cancer therapeutics, biomarkers are in high demand as tools to verify prognosis or to predict patient’s response to molecular-targeted agents. Previously, with the gene expression microarrays we have identified a molecular signature of response to the Hsp90 Inhibitor 17-AAG of breast cancer cell lines, composed of 35 genes. These included chaperons such as Hsp90, Hsp70 or Hsp40, Hsp90 client proteins, transcription and pathway signalling regulators or proteasome ubiquitination components. To further validate the method determining the efficiency of 17-AAG in the treatment of breast cancer we have evaluated the biological effects of 17-AAG on the primary tumor cells and verified the gene expression changes in a set of potential biomarkers using real time RT-PCR. Additionally, we have analyzed the expression of Hsp90 and the cochaperones Hsp70 and Hsp40 in a set of primary tumors by inmunohistochemistry. All these tumors were previously characterized for a number of common markers used to classify breast tumors as Luminal A, Luminal B, Basal and HER2+. Interestingly, in sporadic breast tumors, Hsp70 expression seem to be different among the molecular subgroups showing absence or low expression mainly associated to the HER2+ and Basal-like tumors, the two groups characterized by ER- expression. Association analysis between Hsp70 expression and the tumoral subgroups showed that Hsp70 was significantly (p=0.0369) expressed more frequently in Luminal A and B molecular subtypes of breast cancer when compared to HER2/Basal. In this context, our data strongly suggest that HSP70 might be a recommendable prognostic marker in selection of those patients in which the 17-AAG treatment would be effective.

Hsp70 as a biomarker of response and prognostic marker to Hsp90 inhibitor, 17AAG, in breast tumors

MAGDALENA ZAJAC1, Ivan Muñoz1, Samuel Domingo1, Gonzalo Gomez2, Javier Benitez1,3, Beatriz Martínez-Delgado1,3

1Human Cancer Gentics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain2Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain 3CIBERER, Centre for Biomedical Networking Research on Rare Diseases, Valencia, Spain


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Recent phase I trials with targeted therapies have shown spectacular responses in selected patient populations, in part due to the determination of a “context of vulnerability” (Von Hoff et al), where a greater understanding of the biology of certain cancers has guided the selection of specific patient populations for particular target therapies in early clinical trials.I will discuss our efforts at Vall d’Hebron Institute of Oncology to enrich early clinical trials of targeted agents with those patients more likely to benefit from a specific drug. This task-force includes a Phase I Clinical Trials meeting where each case is debated based on the experience and the literature, testing the tumour for aberrations of the specific target or dysregulation of related signal transduction pathways by different techniques (IHC, IF, FISH, DNA sequencing…), and, in some cases where a sign of activity is seen in a specific disease, an outreach effort with our referring oncologists. I will also discuss the experience of using different platforms for detecting pathway dependence in the development of PI3K inhibitors, and how this effort is changing the population of patients that participate in early clinical trials with such compounds.

Selecting patients for a phase I trial in the era of targeted therapies

JORDI RODON Vall d´Hebron - Institute of Oncology, Barcelona, Spain

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Things will now need to change drastically in the way phase I clinical trials are conducted. Molecular characterization of both patient’s tumors and their normal cells will likely dictate just what the patient should be receiving. This approach will assure patients receive the best treatment for them. Techniques currently being used to find the right new agent for our patient with refractory cancer include immunohistochemistry, DNA microarray, comparative genomic hybridization and soon total sequencing. Utilizing the first technologies we have evidence that 27% of patients whose tumors have progressed on all prior therapies can benefit from a molecular profiling approach. Data will be presented to indicate that profiling of not only the patient’s tumor but the stroma present in the patients’ tumor might provide benefit for the individual patient. In conclusion if we apply the technologies we have now for the patients with refractory cancer now we have a chance of benefitting that patient now.

Sequencing for 6000!

DANIEL D. VON HOFF Translational Genomics Research Institute, Phoenix, USA

Chair: Manuel HidalgoKeynote address


37

Molecular Cancer TherapeuticsChair: Emiliano CalvoApplying biomarkers to clinical cancer research

Functional imaging in drug development

Sequential non-invasive quantitative imaging of key aspects of tumor biology and host-tumor interactions is feasible using Functional Imaging including MRI , SPECT-CT and PET-CT imaging in both preclinical model systems and in humans. Aspects of tumor physiology including vascular permeability , diffusion of water, and tumor energy spectra can be assessed by MRI and MRS. These parameters are of particular interest in assessing treatment response. PET typically is used to image shorter lived biological processes while SPECT is somewhat less quantitative but can image well slower biological processes. Processes imaged with PET and SPECT include tumor glycolysis, amino acid transport, proliferation, oxygenation, blood flow, receptors, and key enzymes. Other agents are examining infiltrating inflammatory cells and transfected reporter genes. Ultrasound has a role in assessing tumor blood flow and repeated assessments of tumor size. Optical imaging is a potent tool in animal model systems but is not as easily translated to humans. This lecture will briefly review the current status of functional imaging in preclinical and clinical studies, with an emphasis on successes and attention to key limitations of the approach. The new PERCIST 1.0 criteria for treatment response on PET will also be briefly introduced.

RICHARD WAHL Johns Hopkins University, Baltimore, USA

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Pharmacodynamic testing enables the characterization of the effect of a pharmacological anticancer intervention on the recipient and the tumor. Whereas this results in valuable information regarding the target specificity of a given drug and associated events, it is limited by efficient assay development and (as opposed to predictive biomarker testing) has yet to be applied to patient selection strategies. Novel approaches such as ex vivo pharmacodynamic testing and multi-compartment subpopulation assessment represent areas of intense research that offer the promise of furthering individualized therapeutics.

Pharmacodynamic testing: New directions

ANTONIO JIMENO Division of Medical Oncology, School of Medicine, University of Colorado at Denver, Aurora, USA

Chair: Emiliano CalvoApplying biomarkers to clinical cancer research


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Phase II randomized study of biomarker-directed treatment for non-small cell lung cancer (NSCLC): The BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) clinical trial program

Treatment for patients with recurrent NSCLC has limited efficacy despite the use of new targeted agents. Identifying biomarkers to predict tumor response will help personalize therapy for individuals. This lecture will describe the MDACC BATTLE program. Eligible patients had prior chemotherapy, ECOG PS 0-2, and when enrolled, required 2 fresh core needle biopsy specimens to test 11 biomarkers related to 4 molecular pathways in NSCLC: EGFR, Kras, and Braf gene mutation (PCR-based sequencing), EGFR and Cyclin D1 copy number analyses (FISH), and 6 proteins via IHC (VEGF/R and RXR receptors/Cyclin D1). Based on eligibility and tumor biomarker analyses, patients were randomized into 1 of 4 treatments: erlotinib (E) 150 mg qd; sorafenib 400 mg bid, vandetanib 300 mg qd; E 150 mg + bexarotene 400 mg/m2 qd. The primary endpoint is 8-week progression-free status. We have demonstrated that biopsies are safe and feasible for biomarker-directed studies. The study recently completed enrollment to 200 evaluable patients. BATTLE is one of the first studies in advanced lung cancer to prospectively utilize biomarker analysis of fresh biopsies to direct pt treatment, and is a step towards personalizing therapy in NSCLC. The follow-up BATTLE-2 study will also be discussed. Supported by grant DoD W81XWH-6-1-0303.

ROY S. HERBSTThe University of Texas MD Anderson Cancer Center, Houston, USA

Chair: Emiliano CalvoApplying biomarkers to clinical cancer research

INVITED SPEAKERSBIOGRAPHIES

Patients

Drugs

Cancer

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Douglas Yee, MD, is the director of the Masonic Cancer Center, University of Minnesota. A professor in the Departments of Medicine and Pharmacology, Dr. Yee holds the John H. Kersey Chair in Cancer Research. His laboratory research is focused on the regulation of cancer cells by the insulin-like growth factors. His work has established the potential for the targeting of this pathway in cancer. Current areas of investigation include the establishment of predictive biomarkers to identify “IGF-driven” tumors and to model rational combination therapies. He has published over 150 articles about breast cancer in scientific journals.

Dr. Yee also maintains an active clinical practice and cares for patients with breast cancer at the Breast Center, University of Minnesota Medical Center, Fairview. He has also served on several review panels including the National Cancer Institute’s Cancer Biomarkers’ Study Section and the Department of Defense Integration Panel. He is a member of the Scientific Advisory Committee, Army of Women, Dr. Susan Love Research Foundation – Avon Foundation, the ADA-ACS Consensus Panel on Diabetes and Cancer, and numerous other peer reviewing panels related to cancer research.

Dr. Yee graduated from the University of Michigan in Ann Arbor, earned his medical degree from the University of Chicago, and completed his residency at the University of North Carolina in Chapel Hill and his fellowship at the National Cancer Institute in Bethesda, MD. Before coming to Minnesota, he held faculty positions at Georgetown University Medical Center in Washington, D.C., and at the University of Texas Health Science Center in San Antonio.

Douglas Yee, MD

Director, Masonic Cancer Center, University of MinnesotaProfessor of Medicine and PharmacologyMinneapolis, MinnesotaUSA


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Alex A. Adjei, MD PhD is Professor of Oncology and Chair, Department of Medicine, as well as Senior Vice-President for Clinical Research at Roswell Park Cancer Institute (RPCI), Buffalo, NY, USA. He is also the Katherine Anne Gioia Chair in Cancer Medicine as well as Professor of Medicine at the State University of New York in Buffalo. He is co-Leader of the Molecular Targets and Experimental Therapeutics Program, and runs the Phase I Program at RPCI.He is Chair of the Lung Cancer Committee of the North Central Cancer Treatment Group. Dr Adjei’s research is focused on development of novel agents for the therapy of solid tumors. In the clinic, his work has focused on the assessment of toxicity, pharmacology, and initial activity of selected agents and regimens in early clinical trials, and development of biomarkers of drug effect as well as phase II clinical trials of novel agents in lung cancer. In the laboratory, his interest is in the elucidation of mechanisms of action and resistance of novel agents that inhibit cell signaling.

Alex Adjei, MD PhD

Professor and Chair, Department of MedicineKatherine Anne Gioia Chair in Cancer MedicineRoswell Park Cancer InstituteBuffalo,USA

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Dr. LoRusso is recognized as an international expert in the field of Phase I clinical research with a focus on novel trial design. The Phase I Program Dr LoRusso has built at Karmanos is one of only 14 National Cancer Institute (NCI) U01 funded sites in the country and the only such in Michigan. The State of Michigan has recognized the importance of the Phase I Program with a grant from the Michigan Economic Development Corporation (MEDC grant for $2.6 million).

Dr. LoRusso serves as Co-Chair of the NCI Cancer Therapy Evaluation Program (CTEP) Investigational Drug Steering Committee. She has also served on the education and scientific committees of the American Society of Clinical Oncology (ASCO), the scientific committee of the American Association for Cancer Research (AACR), and as a parent member of the NCI’s Quick Trials Clinical Subcommittee. She has served either ad hoc or as an appointed member on multiple study sections including subcommittee D of the Program Projects grants, and Small Business Innovation Research (SBIR) and Department of Defense (DOD) study sections. Along with her many research publications; Dr LoRusso has recently contributed chapters to the prestigious oncology texts, The Molecular Basis of Cancer (Mendelsohn J, et al, Eds) and Cancer: Principles & Practice of Oncology (DaVita VT, et al, Eds).

In 1999, Dr LoRusso was awarded the Hero of Breast Cancer award and in 2004 the Bennett J. Cohen Educational Leadership Award for Medical Research. Within the past year, Dr LoRusso received the Marygrove College Distinguished Alumni Award, and was named one of Crain’s Detroit Business Health Care Heroes. She was also recognized with the 2008 Michaele C. Christian Oncology Drug Development Award and Lectureship from NCI CTEP.

Patricia LoRusso, DO

The Barbara Ann Karmanos Cancer InstituteDetroit, USA


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Josep Tabernero received his medical degree from the Universitat Autònoma de Barcelona, Spain. Afterwards, he completed his specialist training in medical oncology and has had appointments in Barcelona.Dr. Tabernero is currently a senior consultant in the Medical Oncology Department at the Vall d’Hebron University Hospital in Barcelona, Spain. He is head of the Gastrointestinal Tumors Unit and is actively involved in translational research and pharmacodynamic phase I studies with molecular targeted therapies and related translational research, with a special focus on EGFR-family inhibitors and IGFR-PI3K-Akt-mTOR pathway inhibitors, and also in phase II and III studies with new chemotherapy agents in gastrointestinal tumors. In addition, Dr. Tabernero is a member of the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO), and different Editorial Boards including the Journal of Clinical Oncology, Clinical Colorectal Cancer and Annals of Oncology. He has (co)authored approximately 120 peer-reviewed papers. He has also been member of the Educational and Scientific Committees of the ESMO, ECCO, ASCO, AACR/NCI/EORTC, ASCO Gastrointestinal, and WCGIC meetings.

Josep Tabernero, MD

Head of the Gastrointestinal Tumors and Phase I UnitMedical Oncology DepartmentVall d’Hebron University HospitalBarcelona, Spain

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Dr Senderowicz is currently Senior Medical Director for clinical research in the Emergent Product Team 3 (EPT3) and Oncology Phase I team (OPIT), Oncology Therapy Area, AstraZeneca since July 2008, when he joined AstraZeneca, Wilmington, DE. Moreover, he is the Global Program Physician for AZD1480 (jak 2 inhibitor). He completed his MD from the University of Buenos Aires, Argentina. He then moved to NYC to complete his Internal Medicine residency at Mount Sinai Hospital, NY. He then moved to the National Cancer Institute (NCI) in Bethesda, Maryland, initially as a clinical fellow and then as Coordinator for Developmental Therapeutics Program Clinical Trials Unit where he lead several Phase I trials with cell cycle modulators in oncology patients. In 2000, he became the Chief of the Molecular Therapeutics Unit, where he led a laboratory dedicated to translational issues in head and neck cancer. In 2004, he moved to the Division of Oncology Drug Products, Office of Oncology Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, initially as a medical officer and then as a clinical team leader. Before joining AZ, he was also Attending Physician at the GI Clinic National Naval Medical Center/NCI.

Adrian Senderowicz, MD

Senior Medical DirectorClinical Research Oncology, Oncology Therapy AreaAstraZenecaWilmington, USA


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Jaap Verweij, MD PhD is Professor of Medical Oncology and chairman of the Department of Medical Oncology of the Erasmus University Medical Centre in Rotterdam, The Netherlands. His main interests are new drug development, including the performance of clinical phase I and early phase II trials, and the inclusion of pharmacokinetics, pharmacodynamics and pharmacogenetics in these studies. He also has a major interest in the design aspects of early clinical studies. Besides his clinical activities he has been the chairman of the Early Clinical Studies Group of the European Organisation for Research and Treatment of Cancer (EORTC) from 1993-1996, chairman of the EORTC Soft Tissue and Bone Sarcoma Group from 1996-1999, chairman of the EORTC New Treatment Committee, the EORTC New Drug Advisory Committee, and Vice-President of EORTC. He has also been president of the Connective Tissue Oncology Society (CTOS). He is editor of the European Journal of Cancer and associate editor of the Journal of Clinical Oncology, past-Chairman of the RECIST working group, and chairman of the Scientific Council of the Dutch Cancer Foundation.

He has authored or co-authored over 700 papers on various aspects, and has given numerous lectures on a variety of topics at international meetings.

Jaap Verweij, MD PhDProfessor of Medical OncologyErasmus University Medical CentreRotterdam, The Netherlands

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Gary M. Clark, PhD is Vice President of Biostatistics & Data Management at Array BioPharma Inc in Boulder, Colorado, USA. He is actively involved in the development of targeted therapies for various cancers. His areas of expertise and interest include the identification and evaluation of prognostic and predictive biomarkers for breast cancer, lung cancer and other solid tumors, and the design and analysis of Phase I, II, III clinical trials of targeted therapies. Prior to joining Array BioPharma in 2008, he was Vice President of Biostatistics & Data Management at OSI Pharmaceuticals, Inc. in Boulder, Colorado where he helped develop and was instrumental in the regulatory approval of a small molecule inhibitor of EGFR tyrosine kinase. Prior to joining OSI Pharmaceuticals in 2002, Dr. Clark served at Baylor College of Medicine in Houston, Texas (1999-2002) as Professor of Medicine and Associate Director of the Breast Center, Director of Tissue Resources, and Director of Informatics. His previous positions included service at the University of Texas Health Science Center at San Antonio, Texas (1980-1999) where he was Professor of Medicine in the Division of Medical Oncology and Director of the Biostatistics, Data Management & Data Processing Shared Resource of the San Antonio Cancer Institute. Dr. Clark has an extensive list of publications in the area of early drug development and has significantly contributed to the field of biomarkers in breast cancer and other solid tumors. He has been a member of numerous committees of the National Cancer Institute, AACR and ASCO, including several grant review and consensus development panels. He was co-director of the AACR/ASCO Workshop on Methods in Clinical Cancer Research in Vail, Colorado from 1996 to 2000, and co-director of the FECS/AACR/ASCO Workshop on Methods in Clinical Research in Flims, Switzerland from 1999 to 2005.

Gary M. Clark, PhD

Vice President, Biostatistics and Data Management Array BioPharmaBoulder, USA


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Eric K. Rowinsky, MD

Adjunct Professor of Medicine, New York University Scientific Consultant, Imclone SystemsChampions Biotechnolc Oncodrugs Consultants New York, USA

Dr. Eric K. Rowinsky is principally focused on the comprehensive development and registration strategies of cancer therapeutics of all types. Dr. Rowinsky received his B.A. degree from New York University and his M.D. from the Vanderbilt University School of Medicine. Following his residency in internal medicine at the University of California, he completed fellowship training in medical oncology and clinical pharmacology at the Johns Hopkins University School of Medicine. From 1987 to 1996, Dr. Rowinsky served as an Associate Professor of Oncology at Johns Hopkins where he performed seminal clinical development and pharmacologic studies on paclitaxel, docetaxel, irinotecan, topotecan, among other agents. From 2006-2004, he served as the Director of Clinical Research and later Director of the Institute for Drug Development of the Cancer Therapy and Research Center in San Antonio where he held the SBC Endowed Chair for Early Drug Development and was a lead investigator on early developmental studies of many classes of targeted therapeutics such as erlotinib, gefitinib, panitumumab, temsirolimus, ridaforolimus, trabectedin, and many other agents. He was also Clinical Professor of Medicine at the University of Texas from 1996-2006. From 2005-2007, Dr. Rowinsky served as the Chief Medical Officer and Executive Vice President at ImClone Systems, responsible for clinical development and regulatory affairs; the company was recently acquired by Eli Lilly. Dr. Rowinsky is currently an Adjunct Professor of Medicine at New York University and currently serves as a Scientific Advisor to Imclone/Eli Lilly, Champions Biotechnology, RRD International, and a wide variety of biotechnology companies.

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Manuel Hidalgo (Antequera, Malaga, 1968) received his MD degree from the University of Navarra, Pamplona, Spain in 1992 and his PhD degree from the University Autonoma of Madrid, Spain in 1997. Subsequently, Dr. Hidalgo trained in Medical Oncology at the University Hospital “12 de Octubre” in Madrid, obtaining his Medical Oncology degree in 1996. Dr. Hidalgo completed a specialized fellowship in Drug Development at the Institute for Drug Development of the University of Texas Health Science Center in San Antonio, USA, where he worked under the mentorship of Eric Rowinsky, Dan Von Hoff and Gail Eckhardt, three world-leaders in drug development. During these years Dr. Hidalgo participated in the early clinical development of erlotinib and temsirolimus, two of the most recently approved anticancer agents. After a brief period as an Assistant Professor at the University of Texas Health Science Center, Dr. Hidalgo joined the Johns Hopkins University Kimmel Cancer Center in 2001 were he was co-director of the drug development and GI programs. During these years at Hopkins his work concentrated on novel therapies for patients with pancreas cancer. In 2003, Dr. Hidalgo and other colleagues founded the Pancreatic Cancer Research Team (PCRT), a cooperative clinical trials group that focuses on novel therapeutics for patients with pancreatic cancer. In 2006, Dr. Hidalgo became the Director of the Centro Integral Oncologico ¨Clara Campal¨ in Madrid Spain as well as Professor of Oncology at the Universidad CEU San Pablo in Madrid. In combination with the former activities, Dr. Hidalgo joined the CNIO in 2009 to head the Gastrointestinal Cancer Clinical Research Unit and serve as acting Director of the Clinical Research Programme. Dr. Hidalgo’s research interests are in drug development with a particular emphasis on GI malignancies. He has published over 150 papers and book chapter and his research has been uninterruptedly funded for the last 10 years by the NCI, AACR, and ASCO and other funding agencies. At the CNIO, Dr. Hidalgo will lead a research group focusing on novel therapeutics for patients with gastrointestinal cancer. This group aims to conduct innovative clinical research with rationally designed molecules targeting genetic abnormalities in this group of cancers.

Manuel Hidalgo, MD PhD

Head of the Gastrointestinal Cancer Clinical Research UnitDirector of the Clinical Research Programme Spanish National Cancer Research Centre (CNIO), Madrid, Spain

Director, Centro Integral Oncológico Clara Campal (CIOCC)Assistant Professor of Oncology, CEU Universidad San Pablo, Madrid, Spain


53


Elizabeth Garrett-Mayer, PhD

Director of Biostatistics Hollings Cancer CenterAssociate Professor of BiostatisticsMedical University of South CarolinaCharleston, USA

Elizabeth Garrett-Mayer, PhD, is Director of Biostatistics at the NCI-designated Hollings Cancer Center (HCC) at the Medical University of South Carolina, Charleston, SC, USA. She received her PhD in Biostatistics from The Johns Hopkins University (JHU). She served for seven years as a member and for one year as the chair of the Scientific Clinical Review Committee for the JHU Cancer Center and is a member of both the Protocol Review and Data Safety and Monitoring Committees at HCC. She has co-authored more than 140 peer-reviewed papers. Her research interests are in adaptive designs in early phase cancer research.

Dr. Rowinsky is the Editor-in-Chief of Investigational New Drugs, an Associate Editor and Editorial Board Member of Cancer Research (Associate Editor and Reviews Editor), Clinical Cancer Research, Annals of Oncology, Cancer Biology and Therapy and several other oncology journals and has published approximately 300 manuscripts in both the preclinical and clinical research fields. He has also served on the Board of Directors, Scientific Advisory Board and Project Advisory Boards of a large number of pharmaceutical and biotechnology companies and has advised and/or presented aspects of New Drug Applications to the FDA on several occasions. Dr. Rowinsky’s honors include receipt of the career development award of the American Cancer Society and the 6th Annual Emil J. Freireich Award for outstanding achievement of a young researcher in clinical cancer therapeutics. He has also served on the Board of Scientific Counselors of the NCI.

54


Dr. Lillian Siu is a staff physician in the Department of Medical Oncology and Hematology at Princess Margaret Hospital since 1998, and is a professor at the University of Toronto. Dr. Siu is Director of the Phase I Program and Co-Director of the Robert and Maggie Bras and Family Drug Development Program at Princess Margaret Hospital.

Dr. Siu’s major research focus is in the area of new anticancer drug development, particularly with respect to phase I trials, head and neck and neuroendocrine malignancies. She is principal investigator of many clinical trials supported by NCI, NCIC and the pharmaceutical industry. She is the principal investigator of a phase I cooperative agreement U01 award (2008-2013) sponsored by the United States NCI which aims to expedite the access and evaluation of novel anti-cancer agents for patients, optimize clinical trials design of new agents, and characterize the molecular effects of new agents on their targets.

Dr. Siu is the recipient of numerous awards such as the Elsie Winifred Crann Award at the University of Toronto in 2001. Internationally, Dr. Siu has been a member of the AACR International Membership Committee, the ASCO Head and Neck Cancer Scientific Program Subcommittee, and the EORTC Protocol Review Committee. Dr. Siu is the current Neuroendocrine Tumor Task Force Chair in the North American Gastrointestinal Intergroup Scientific Steering Committee. In 2009, Dr. Siu has been awarded a Cancer Care Ontario Tier 1 Chair in Experimental Therapeutics. Dr. Siu has a strong background in clinical trial methodology and has been a member of the Program Committees for both the FECS/ASCO/AACR workshop in Flims, Switzerland and the AACR/ASCO workshop in Vail, Colorado. Dr. Siu has published over 100 peer-reviewed manuscripts, she is currently an editor for European Journal of Cancer and has been on the Editorial Board of Journal of Clinical Oncology.

Lillian L. Siu, MD FRCPC

Professor, University of TorontoCCO Research Chair, Experimental TherapeuticsMedical Oncologist, Princess Margaret HospitalDrug Development ProgramToronto, OntarioCanada


55


Emiliano Calvo, MD PhD

Director, Clinical ResearchSTART Madrid, Centro Integral Oncológico Clara Campal (CIOCC),Medical Oncology DivisionHospital Universitario Madrid Norte SanchinarroMadrid, Spain

Emiliano Calvo is the Director of Clinical Research at the Centro Integral Oncológico Clara Campal and Head of the START Madrid program of Early Clinical Development in Madrid, Spain. Dr Calvo received his medical degree from the Universidad Autónoma de Madrid in Madrid (1993) and his Doctorate in Philosophy from the Universidad de Navarra in Pamplona, Spain (2003). Between 2005 and 2008, he was working in the Medical Oncology Department at the Hospital Vall d’Hebron in Barcelona, Spain, where he headed the Genitourinary Tumor Area from 2006 until 2008, the Pharmacokinetics Unit from 2005 until 2008, and was Co-Director and Senior Researcher of the Phase I Unit. Before, from 2003 until 2005 he was a Senior Fellow and Clinical Investigator in Medical Oncology at the Cancer Therapy & Research Center’s Institute for Drug Development in San Antonio, TX. He is an author on more than 100 scientific articles, abstracts, and oncology book chapters and a reviewer for several international peer-reviewed oncology journals. Dr Calvo is an active member of the European Organisation for Research and Treatment of Cancer, American Society of Clinical Oncology, and European Society for Medical Oncology (ESMO); a faculty member of the Educational Committee of ESMO, at the Clinical Trials and Systemic Therapy Group; and a member of the Scientific Committee of the ESMO/ECCO (European Cancer Organization) Annual meetings, from 2008 to 2011. His research is focused on anticancer clinical drug development, and he has participated as an investigator in more than 70 clinical trials, most of them Early Clinical Trials.

56


Dr. Pusztai leads the pharmacogenomic program in the Department of Breast Medical Oncology at MD Anderson Cancer Center. He received his MD degree from the Semmelweis University of Medicine in Budapest his D.Phil. from the University of Oxford in England, he is currently Professor of Medicine. He is a practicing medical oncologist and clinical researcher who published over 130 peer-reviewed articles on the biology and treatment of breast cancer. His research focuses on the developing pharmacogenomic markers of response to therapy and identifying methods to select the optimal treatment for individual patients. His group has proposed new clinical trial designs for predictive marker evaluation, introduced new pathologic measurements of residual cancer after neoadjuvant chemotherapy, created web-based chemotherapy response prediction models based on routine clinical variables and proposed genomic markers of chemo- and endocrine-therapy sensitivity. Dr Pusztai is principal investigator of several clinical trials investigating new drugs and potential response markers. His research is supported by grants from the National Cancer Institute, the US Department of Defense, the American Society of Clinical Oncology, the Breast Cancer Research Foundation and philanthropic research grants.

Lajos Pusztai, MD DPhil

The University of Texas MD Anderson Cancer CenterHouston, USA


57


Charles Rudin, MD PhD

Professor and DirectorUpper Aerodigestive Cancer Program Associate Director for Clinical ResearchThe Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, USA

Dr. Rudin is the Associate Director for Clinical Research for the cancer center at Johns Hopkins, where he also directs the Upper Aerodigestive Cancer Program and serves as Clinical Director of the Hopkins lung cancer SPORE. Dr. Rudin leads the Johns Hopkins FAMRI Center of Excellence in Translational Research focused on tobacco-related disease. He is a member of three graduate training programs, in Clinical & Molecular Medicine, Pharmacology, and Cancer Epidemiology Prevention, & Control. Dr. Rudin has focused on development and testing of novel cancer therapeutics related to his basic and translational laboratory work on lung cancer. Several novel treatment strategies, including re-expression of genes silenced in cancer, targeting of cancer cell death pathways, systemic administration of a cancer-specific virus, and targeting of embryonic developmental signaling pathways are being studied in parallel in the Rudin laboratory and in early phase clinical trials in patients with lung cancer and other solid tumors. Dr. Rudin serves as a member of the ECOG Thoracic Core Committee and Lung Cancer Biology Subcommittee, the Intergroup Correlative Sciences Committee for Lung and Thoracic Cancers, the ASCO Cancer Research Committee, and the NCI Investigational Drug Steering Committee. Dr. Rudin was a standing member of the NIH Clinical Oncology (CONC) Study Section, and has been on the editorial boards of the Journal of Clinical Oncology, Investigational New Drugs, and Cancer Prevention Research. Awards include the Annals of Oncology Prize for the best article on early phase clinical research published in the previous 2 years, and the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research.

58


Dr. Johann de Bono MD FRCP MSc PhD was appointed in 2003, as Senior Lecturer and Honorary Consultant in Medical Oncology in the Section of Medicine at the Royal Marsden Hospital and Institute of Cancer Research, which form Europe’s largest Comprehensive Cancer Centre. He plays a leading role in the clinical drug development Phase I trials program at the Royal Marsden Hospital, is a key translational clinician in the Centre for Cancer Therapeutics, and plays a major role in the Academic Urology team treating patients with castration resistant prostate cancer. He has a particular interest in the rational design of molecular targeted therapies for prostate cancer.

Between 2000 and 2003 he was researching and developing new anticancer drugs in the USA at the Institute for Drug Development in San Antonio and the University of Texas Health Science Centre at San Antonio. Dr de Bono has been involved in the development of over 50 novel agents over the last 5-years, several of which have now been approved. He is currently running over 20 early clinical trials.

Johann de Bono, MD FRCP PhD MSc

Reader in Experimental Cancer Medicine & Honorary Consultant Medical OncologistRoyal Marsden NHS Foundation Trust and Institute of Cancer ResearchSutton, UK


59


S. Gail Eckhardt, MD

Professor and Division Head, Division of Medical Oncology, University of Colorado DenverProgram Leader, Developmental Therapeutics Programme, University of Colorado Comprehensive Cancer Center, Aurora, USA

S. Gail Eckhardt, MD is Professor and Head of the Division of Medical Oncology at the University of Colorado at Denver where she also holds the Stapp / Harlow Endowed Chair for Cancer Research and is Program Leader for Developmental Therapeutics at the University of Colorado Comprehensive Cancer Center.

Dr. Eckhardt received her medical degree from the University of Texas Medical Branch in Galveston followed by an internship and residency at the University of Virginia Medical Center. After a post-doctoral fellowship at the Scripps Research Foundation, she completed her training in medical oncology at the University of California at San Diego. Following fellowship, Dr. Eckhardt joined the faculty of the Cancer Therapy and Research Center, Institute for Drug Development in San Antonio, Texas where she held the position of Associate Director of Clinical Research. In 1999, Dr. Eckhardt joined the faculty of the University of Colorado to set up a Phase I program and is currently a tenured Professor there.

Dr. Eckhardt has served on numerous committees, including the ASCO Molecular Oncology Task Force, the ESMO Translational Research Working Group, ASCO Board of Directors, the FDA Oncology Drugs Advisory Committee (current Chair), and NCI Gastrointestinal Steering Committee. In addition, Dr. Eckhardt has been an Associate Editor of Clinical Cancer Research, the Journal of Clinical Oncology, and Investigational New Drugs.

Dr. Eckhardt holds peer-reviewed funding for early clinical trials, mentoring, and colorectal cancer research and has conducted numerous phase I and II clinical trials. She has published over 110 manuscripts and serves on numerous advisory boards. Her area of interest is in the preclinical and clinical development of predictive biomarkers for novel agents and rational combinations of molecularly targeted compounds using a comprehensive systems approach. Although her focus is on colorectal cancer, others in the lab are working on melanoma and breast cancer.

60


Daniel D. Von Hoff, MD, is an internationally recognized physician-scientist who has contributed to the development of numerous anticancer agents. Together with his colleagues, he was involved in the development of many of the agents now routinely used in cancer care including paclitaxel, docetaxel, irinotecan, gemcitabine and many others. Dr. Von Hoff ’s laboratory interests have been in the area of individualizing treatment for the patient. He and his laboratory are also concentrating on the discovery of new targets in pancreatic cancer. Dr. Von Hoff serves as Physician in Chief for the Translational Genomics Research Institute (TGen) in Phoenix, Arizona and Chief Scientific Officer of Scottsdale Healthcare and US Oncology. He is also Clinical Professor of Medicine at The University of Arizona College of Medicine. Dr. Von Hoff received his medical degree from the Columbia College of Physicians and Surgeons in New York and completed his residency at the University of California, San Francisco. Dr. Von Hoff is a past president of the American Association for Cancer Research, past Board Member of ASCO and a fellow of the American Association for the Advancement of Science and the National Foundation for Cancer Research. In 2004, he was appointed to President Bush’s National Cancer Advisory Board.

Dan Von Hoff, MD

Translational Genomics Research Institute,Phoenix, USA


61


Richard L. Wahl, M D is Professor of Radiology and Oncology, as well as the Henry N. Wagner, Jr. Professor of Nuclear Medicine at Johns Hopkins University. He is Director of Nuclear Medicine, PET and the Vice Chair of Radiology for Technology and New Business Development. Dr. Wahl received his MD degree at Washington University in St. Louis and most of his post doctoral training in Radiology and Nuclear Medicine at the Mallinckrodt Institute of Radiology. He pioneered the development of PET in oncology in both preclinical and clinical studies showing the feasibility of the method in both cancer diagnosis, staging and treatment response in a wide range of cancers. He and his colleague Chuck Meyer developed anatometabolic image fusion, fusion of PET with CT , SPECT or MRI into hybrid images. He also is one of the inventors of radioimmunotherapy of lymphoma with anti CD20 antibodies, methods underlying the drugs Bexxar and Zevalin. He and his colleagues have published approximately 350 articles and has published several books on PET, PET/CT and SPECT/CT. He is also a senior consultant to the Tawam Molecular Imaging Center.

Richard Wahl, MD

Johns Hopkins PET Center University, Baltimore, USABaltimore, USA

62


Antonio Jimeno, MD PhD

Assistant ProfessorDivision of Medical OncologySchool of MedicineUniversity of Colorado at DenverAurora, USA

Dr. Jimeno joined the University of Colorado Denver Faculty in April 2008 as the Director of the Developmental Therapeutics/Pharmacodynamic Laboratory and as a member of the Drug Development Program and Stem Cell Programs. Dr. Jimeno has an interest in integrating preclinical research, drug development, and clinical research with a focus in Head and Neck Cancer and other tobacco related cancers. His aim is to bridge the lab and the clinic by 1) developing patient-derived models of cancers as a platform to study cancer stem cells, 2) conducting preclinical tests of targeted agents against de-regulated pathways and cancer stem cells, and 3) devising ways to integrate that knowledge into clinical trials to individualize anti-cancer therapy. His concomitant work in the laboratory and the clinic has materialized in the form of novel inventions (drugs and biomarkers) that are currently the subject of prospective clinical testing.


63


Roy S. Herbst, MD PhD is a professor of medicine and the chief of the section of thoracic medical oncology in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas M. D. Anderson Cancer Center in Houston, Texas, where he is the Barnhart Family Distinguished Professor in Targeted Therapies. Dr. Herbst holds a B.S. and M.S. in molecular biophysics and biochemistry from Yale University, an M.S. in clinical translational research from Harvard University, and a Ph.D. in molecular cell biology from The Rockefeller University. He received his M.D. from Cornell University Medical College and completed fellowship training in medicine, medical oncology, and medical hematology at the Dana Farber Cancer Institute, Harvard School of Medicine. Dr. Herbst is the principal investigator for numerous clinical trials and has conducted research primarily in the treatment of lung cancer, head and neck cancer, and phase I studies. His work has focused on the clinical development of molecular targeted therapies for lung cancer and a better understanding of the molecular predictive markers for their use as personalized therapy. . He has authored and co-authored more than 250 publications, including peer-reviewed journal articles, abstracts, and book chapters. Dr. Herbst is the former chairman of the American Society of Clinical Oncology (ASCO) Cancer Communication Committee and now serves on the ASCO nominating committee. He serves on the editorial board of several peer-reviewed journals, including the Journal of Clinical Oncology and Clinical Lung Cancer where he is a senior editor. He is the chair of the AACR Tobacco Task Force. He is the co-principal investigator of the M. D. Anderson Department of Defense Lung Cancer Program where he is the co-principal investigator of the IMPACT and BATTLE programs. He leads the CCSG Lung Cancer program at M.D. Anderson and is the principal investigator for the SWOG U10 grant. Dr. Herbst is the recipient of numerous honors and awards, including the Dana Farber Cancer Institute Thoracic Oncology Research Award, the ASCO Young Investigator Award, the ASCO Career Development Award, the Irwin H. Krakoff Award for Excellence in Clinical Research, the David Ben Guiron Leadership Award, the New Frontiers Award, American Society of Cytopathology, and the M. D. Anderson Cancer Center Physician Scientist Program Award.

Roy S. Herbst, MD

The University of Texas MD Anderson Cancer CenterHouston, USA

66



67


LIST OF INVITED SPEAKERS, SHORT TALK SPEAKERS AND ORGANISERS

Patients

Drugs

Cancer

68


Alex AdjeiProfessor and Chair, Department of Medicine, Katherine Anne Gioia Chair in Cancer Medicine, Roswell Park Cancer Institute, Buffalo, [email protected]

Emiliano CalvoDirector, Clinical Research, START Madrid, Centro Integral Oncológico Clara Campal; Medical Oncology Division, Hospital Universitario Madrid Norte Sanchinarro, Madrid, [email protected]

Gary ClarkVice President, Biostatistics & Data Management, Array BioPharma, Boulder, [email protected]

Johann de BonoReader in Experimental Cancer Medicine & Honorary Consultant Medical Oncologist Royal Marsden NHS Foundation Trust and Institute of Cancer ResearchSutton, [email protected]

S. Gail EckhardtProfessor and Division Head, Division of Medical Oncology, University of Colorado Denver; Program Leader, Developmental Therapeutics Programme, University of Colorado Comprehensive Cancer Center, Aurora, [email protected]

Elizabeth Garrett-MayerDirector of Biostatistics, Hollings Cancer Center ; Associate Professor of Biostatistics, Medical University of South Carolina, Charleston, [email protected]


69


Cristina Gómez-AbadLymphoma Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, [email protected]

Christopher Heeschen Stem Cells and Cancer Clinical Research Group, Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, [email protected]

Roy S. HerbstProfessor of Medicine; Chief, Section of Thoracic Medical Oncology, Department of Thoracic/Head and Neck Medical Oncology, Barnhart Family Distinguished Professor in Targeted Therapies, The University of Texas M. D. Anderson Cancer Center, Houston, [email protected]

Manuel HidalgoDirector of the Clinical Research Programme, Head of the Gastrointestinal Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO); Director, Centro Integral Oncológico Clara Campal (CIOCC), Assistant Professor of Oncology, CEU Universidad San Pablo, Madrid, [email protected]

Antonio Jimeno Assistant Professor, Division of Medical Oncology, School of Medicine, University of Colorado at Denver, Aurora, [email protected]

Patricia LoRussoThe Barbara Ann Karmanos Cancer Institute, Detroit, [email protected]

Lajos PusztaiProfessor of Medicine, The University of Texas MD Anderson Cancer CenterDepartment of Breast Medical Oncology, Houston, [email protected]

70


Miguel Quintela-Fandino Breast Cancer Clinical Research Unit, Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, [email protected]

Jordi Rodon Vall d´Hebron - Insitute of Oncology, Barcelona, [email protected]

Eric RowinskyAdjunct Professor of Medicine, New York University; Scientific Consultant,Imclone Systems, Champions Biotechnology, Oncodrugs Consultants, New York, [email protected]

Charles RudinCo-Director, Upper Aerodigestive Cancer Program, Associate Director for Clinical Research, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, [email protected]

Adrian SenderowiczSenior Medical Director, Clinical Research Oncology Oncology Therapy Area,AstraZeneca, Wilmington, [email protected]

Lillian SiuProfessor, University of Toronto, CCO Research Chair, Experimental TherapeuticsMedical Oncologist, Princess Margaret Hospital, Drug Development Program, Toronto, Ontario, [email protected]


71


Josep TaberneroHead of the Gastrointestinal Tumors and Phase I Unit, Medical Oncology Department, Vall d’Hebron University Hospital, Barcelona, [email protected]

Jaap VerweijProfessor of Medical Oncology, Erasmus University Medical Centre, Rotterdam, The [email protected]

Dan Von HoffTranslational Genomics Research Institute, Phoenix, [email protected]

Richard WahlJohns Hopkins University, Baltimore, [email protected]

Magdaleja Wozniak Lymphoma Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, [email protected]

Doug Yee Director, Masonic Cancer Center, University of Minnesota, Professor of Medicine and Pharmacology, Minnesota, [email protected]

Magdalena Zajac Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, [email protected]

CALENDAR 2010

74


2009The energy of cancer02/11/2009 - 04/11/2009Organisers: Toren Finkel, David M. Sabatini, Manuel Serrano and David A. Sinclair

Cancer-om-atics: Multilevelinterpretation of cancer genome data06/07/2009 - 8/07/2009Organisers: Søren Brunak, Nuria Malats, Chris Sander and Alfonso Valencia

Stem cells and cancer23/02/2009 - 25/02/2009Organisers: Elaine Fuchs, Maria A. Blasco, Eduard Batlle and Mirna Perez-Moreno

2008Signalling upstream of mTOR03/11/2008 - 05/11/2008Organisers: Dario R. Alessi, Tomi P. Mäkelä and Montserrat Sanchez-Cespedes

Structure and mechanisms of essential complexes for cell survival23/06/2008 - 25/06/2008Organisers: Niko Grigorieff, Eva Nogales and Jose María Valpuesta


75


Development and cancer04/02/2008 - 06/02/2008Organisers: Konrad Basler, Ginés Morata, Eduardo Moreno and Miguel Torres

2007Links between cancer, replication stress and genomic integrity05/11/2007 - 07/11/2007Organisers: Oskar Fernández-Capetillo, Jiri Lukas, Juan Méndez and André Nussenzweig

Myc and the transcriptional control of proliferation and oncogenesis11/06/2007 - 13/06/2007Organisers: Robert N. Eisenman, Martin Eilers and Javier León

Molecular mechanisms in lymphoid neoplasm19/02/2007 - 21/02/2007Organisers: Elias Campo, Riccardo Dalla-Favera, Elaine S. Jaffe and Miguel Angel Piris

2006Telomeres and telomerase - CNIO / Joséf Steiner Cancer Conference13/11/2006 - 15/11/2006Organisers: María A. Blasco and Jerry Shay

76


Medicinal chemistry in oncology02/10/2006 - 04/10/2006Organisers: Fernando Albericio, James R. Bischoff, Carlos García-Echeverria and Andrew Mortlock

Inflammation and cancer22/05/2006 - 24/05/2006Organisers: Curtis Harris, Raymond DuBois, Jorge Moscat and Manuel Serrano

PTEN and the AKT route08/05/2006 - 10/05/2006Organisers: Ana Carrera, Pier Paolo Pandolfi and Peter Vogt

2005Cancer and aging07/11/2005 - 09/11/2005Organisers: María A. Blasco, Kathy Collins, Jan Hoeijmakers and Manuel Serrano

MAP kinases and cancer30/05/2005 - 01/06/2005Organisers: Philip Cohen, Roger Davis, Worcester, Chris Marshall and Ángel Nebreda

Animal tumour models and functional genomics 07/03/2005 - 09/03/2005 Organisers: Allan Balmain, Mariano Barbacid, Anton Berns and Tyler Jacks


77


2004Cadherins, catenins and cancer29/11/2004 - 01/12/2004Organisers: Amparo Cano, Hans Clevers, José Palacios and Franz Van Roy

Structural biology of cancer targets27/09/2004 - 29/09/2004Organisers: Ernest Laue, Guillermo Montoya and Alfred Wittinghofer

2003Apoptosis and cancer01/12/2003 - 03/12/2003Organisers: Gabriel Nuñez, Marisol Soengas and Scott Lowe

Small GTPases in human carcinogenesis16/06/2003 - 18/06/2003Organisers: Juan Carlos Lacal, Channing Der and Shuh Narumiya

Targeted search for anticancer drugs17/03/2003 - 19/03/2003Organisers: Amancio Carnero and David H. Beach

78


2002Mechanisms of invasion and metastasis18/11/2002 - 20/11/2002Organisers: Joan Massagué and Richard Hynes

The cell cycle and cancer30/09/2002 - 02/10/2002Organisers: Marcos Malumbres, Charles Sherr and Jiri Bartek

Cancer epigenetics: DNA methylation and chromatin29/05/2002 - 31/05/2002Organisers: Manel Esteller and Stephen B. Baylin

As a non-profit organisation, we would like to thank all those who sponsored this conference. Such contributions help us to ensure

that our conferences will continue to establish the CNIO as a point of reference for the international cancer research community.

For information on opportunities to sponsor conferences held at the CNIO, please contact us ([email protected]).

Under the auspices of:

CNIO Centro Nacional de Investigaciones OncológicasMelchor Fernández Almagro, 3

28029 Madridwww.cnio.es

Coordination and edition: Danielle RouseDirection of art and production: Versus

Photographic archive: CNIO

This work is subject to copyright. All rights are reserved whether the whole or part of the material is concerned,

specifically the rights of translation, reproduction on microfilms or in any other way and storage in data banks.

© Fundación CNIO Carlos III, 2010

Printed in Spain

CNIO FRONTIERS MEETING 2010

Melchor Fernández Almagro, 328029 Madrid - SpainTel.: (+34) 91 224 69 00www.cnio.es

Alex Adjei, Roswell Park Cancer Institute,Buffalo, USAEmiliano Calvo, Centro Oncológico Clara Campal,Madrid, SpainGary Clark, Array BioPharma,Boulder, USAJohann de Bono, Institute of Cancer Research and Royal Marsden NHSFoundation Trust, Sutton, UKElizabeth Garrett-Mayer, Medical University of South Carolina,Charleston, USAAntonio Jimeno, University of Colorado Cancer Center, Aurora, USAPatricia LoRusso, The Barbara Ann Karmanos Cancer Institute,Detroit, USALajos Pusztai, The University of Texas MD Anderson Cancer Center,Houston, USAEric Rowinsky, ImClone Systems,New York, USA

Speakers:Charles Rudin, The Johns Hopkins University,Baltimore, USAAdrian Senderowicz, AstraZeneca,Philadelphia, USALillian Siu, Ontario Cancer Institute,Toronto, CanadaJosep Tabernero, Vall d’Hebron University Hospital,Barcelona, SpainJaap Verweij, Erasmus University Medical Center,Rotterdam, The NetherlandsDan Von Hoff, Translational Genomics Research Institute,Phoenix, USARichard Wahl, The Johns Hopkins PET Center,Baltimore, USADoug Yee, University of Minnesota,Minneapolis, USA

Under the auspices of:

8 -10 march 2010 molecular cancer therapeutics · adrian senderowicz, astrazeneca, philadelphia,...

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