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Regions of low oxygen concentration (hypoxia) within solid tumors are a prevalent feature of the cancer phenotype. Both chronic (diffusion-limited) and acute (perfusion-limited) tumor hypoxia have been described and both types of tumor hypoxia are due to abnormal aspects of tumor vasculature. The extent and magnitude of tumor hypoxia has been shown in multiple clinical studies to be a negative prognostic factor for survival. This is thought to be due to two key factors: (a) hypoxic tumor cells are able to resist conventional chemo- and radiation-therapies; and (b) hypoxic tumors are more invasive and metastatic. Transformation into a more invasive and metastatic tumor phenotype is believed to be driven by hypoxia-induced (a) genetic and epigenetic changes; (b) resistance to apoptosis; (c) induction of growth and survival factors; (d) increase in the production of extracellular matrix degrading enzymes that promote invasiveness and migration; (e) maintenance of cancer stem cell identity; (f) induction of the epithelial-mesenchymal transition (EMT); and (g) induction of angiogenesis and neovascularization. Hypoxia has also been shown to be associated with hematological malignancies and the bone marrow niches of leukemia and multiple myeloma. Hypoxic tumor cells are increasingly thought to be an attractive target for the discovery and development of novel cancer therapies; tumor hypoxia plays a central role in cancer progression and treatment resistance, and it provides a basis for selective targeting of tumor cells while sparing normoxic cells elsewhere in the body. A very promising therapeutic strategy is the use of hypoxia-activated prodrugs (HAPs), which enable the selective delivery of cytotoxic or cytostatic agents to hypoxic tumor cells. Furthermore, the development of non-invasive techniques for imaging tumor hypoxia (through PET and EPRI/MRI-based imaging approaches) will allow patient selection to identify those most likely to benefit from HAP therapy. The objective of this symposium is to provide a review of recent highlights in the study of the role of hypoxia in cancer, current advances in the discovery and development of drugs selectively targeting hypoxic cancer cells, and patient profiling approaches employing imaging or circulating or tissue biomarkers of hypoxia.
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Agenda
* Presentation times are subject to change.
Wednesday, March 14, 2012
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12:30 PM
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Registration
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1:00 PM
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Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
George Zavoico, PhD, MLV
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1:10 PM
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A Critical Evaluation of Methods for Imaging Tumor Hypoxia
Mark W. Dewhirst, DVM, PhD, Duke University Medical Center
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1:50 PM
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Targeting Hypoxic Cell Signaling for Cancer Therapy
Giovanni Melillo, MD, Bristol-Myers Squibb
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2:30 PM
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Molecular Imaging of Hypoxia
Hartmuth C. Kolb, PhD, Siemens Healthcare USA
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3:10 PM
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Coffee Break
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3:40 PM
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NLCQ-1 (NSC 709257): A Weak DNA-intercalating Bioreductive Agent. An Overview and New Prospects
Maria V. Papadopoulou, PhD, NorthShore University HealthSystem, University of Chicago
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4:20 PM
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Selective Targeting of Hypoxic Cancer Cells with the Hypoxia-activated Prodrug TH-302: Preclinical and Clinical Studies
Charles P. Hart, PhD, Threshold Pharmaceuticals
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5:00 PM
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Networking Reception
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6:00 PM
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Program Ends
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Speakers
Organizers
Kenneth P. Olive, PhD
Columbia University Medical Center
Dr. Kenneth P. Olive began his doctoral studies in 1998 with Tyler Jacks at the MIT Center for Cancer Research, investigating the neomorphic effects of mutant p53 in a mouse model of Li-Fraumeni Syndrome. While at MIT, he also helped develop a conditional mutant model of advanced lung adenocarcinoma. After graduating in 2005, Dr. Olive began a postdoctoral fellowship in the laboratory of David Tuveson at the University of Pennsylvania, later moving with the lab to the University of Cambridge in England. There he built a translational research facility for studying novel anticancer therapeutics in genetically engineered mouse models of pancreatic cancer. His studies into chemoresistance and the effects of Hh pathway inhibitors on drug delivery in pancreatic cancer were published in Science in 2009, and have led to multiple clinical trials to evaluate the approach in patients with metastatic pancreatic cancer. In 2010, Dr. Olive joined the faculty of the Columbia University Herbert Irving Comprehensive Cancer Center, where he has established a laboratory dedicated to translational science and experimental therapeutics in pancreatic ductal adenocarcinoma.
Barry Selick, PhD
Threshold Pharmaceuticals
Harold E. "Barry" Selick, Ph.D. joined Threshold Pharmaceuticals as its Chief Executive Officer in June 2002. Between June 2002 and July 2007, Dr. Selick was also a Venture Partner of Sofinnova Ventures, Inc., a venture capital firm located in San Francisco, CA. From January 1999 to April 2002, he was Chief Executive Officer of Camitro Corporation, a biotechnology company that was acquired by ArQule in 2001. From 1992 to 1999, he was at Affymax Research Institute, the drug discovery technology development center for Glaxo Wellcome plc, most recently as Vice President of Research. Prior to joining Affymax, he held research positions at Protein Design Labs, Inc. and Anergen, Inc. As a staff scientist at Protein Design Labs, he co-invented the technology underlying the creation of fully humanized antibody therapeutics and applied that to PDL's first product, Zenapax, which was developed and commercialized by Roche for the prevention of kidney transplant rejection. Dr. Selick received his B.S. in Biophysics and Ph.D. in Cell Biology from the University of Pennsylvania and was a Damon Runyon-Walter Winchell Cancer Fund Fellow and an American Cancer Society Senior Fellow at the University of California, San Francisco. Dr. Selick currently serves on the board of directors of Threshold Pharmaceuticals, Protein Design Labs, Protagonist Therapeutics, and Catalyst Biosciences.
George B. Zavoico, PhD
MLV
George B. Zavoico, PhD, is Managing Director, Research, and a Senior Equity Research Analyst at MLV, a boutique investment bank and institutional broker-dealer based in New York. He has over 6 years of experience as a life sciences analyst writing research on publicly traded equities. Prior to MLV, he was an equity analyst with Westport Capital Markets and Cantor Fitzgerald. Prior to working as an analyst, Dr Zavoico established his own consulting company serving the biotech and pharmaceutical industries by providing competitive intelligence and marketing research, due diligence services, and guidance in regulatory affairs. He also wrote extensively on healthcare and the biotech and pharmaceutical industries for periodicals targeting the general public and industry executives. Dr Zavoico began his career as a Senior Research Scientist at Bristol-Myers Squibb Co., moving on to management positions at Alexion Pharmaceuticals, Inc. and T Cell Sciences, Inc. (now Celldex Therapeutics, Inc.). He has a BS in Biology from St. Lawrence University and PhD in Physiology from the University of Virginia and has held post-doctoral positions at the University of Connecticut Health Sciences Center and Brigham and Women’s Hospital and Harvard Medical School.
Jennifer Henry, PhD
The New York Academy of Sciences
Speakers
Mark Dewhirst, DVM, PhD
Duke University Medical Center
Mark W. Dewhirst, DVM, PhD is the Gustavo S. Montana Professor of Radiation Oncology and Associate Dean for Faculty Mentoring in the School of Medicine, Duke University. Dr. Dewhirst has more than 30 years of NIH funding to study tumor hypoxia, angiogenesis, drug transport and hyperthermia. Imaging has been a central component of his research, spanning the range from intravital microscopy to clinical applications. Dr. Dewhirst has well over 500 peer-reviewed publications, book chapters and reviews. He has given named lectures at the University of Western Ontario, Thomas Jefferson University and the New Zealand Cancer Society and was awarded the Failla Medal and Lecture at the Radiation Research Society in 2008, the Eugene Robinson award for excellence hyperthermia research in 1992 and a similar award from the European Society for Hyperthermic Oncology in 2009. He is a Senior Editor of Cancer Research and Editor-in-Chief of the International Journal of Hyperthermia. He has mentored over 60 graduate students, medical students, postdoctoral fellows, residents and junior faculty. He has been particularly skillful in assisting those he has mentored to obtain DOD and NIH fellowships, K awards and first R01 grants. His skill in mentoring has been recognized by the Duke Comprehensive Cancer Center, the Medical Physics Graduate Training programs and the School of Medicine, where he has received "Mentor of the Year" awards. He also was named a Fellow of the American Society for Radiation Oncology on the basis of his mentoring skills and became a fellow of the AAAS in 2011 on the basis of his groundbreaking research in hyperthermia. He graduated from the University of Arizona in 1971 with a degree in Chemistry and Colorado State University in 1975 and 1979 with DVM and PhD degrees, respectively.
Charles P. Hart, PhD
Threshold Pharmaceuticals
Charles Hart joined Threshold Pharmaceuticals in 2004 and became Vice President of Biology in 2008. He is responsible for both in vitro and in vivo preclinical translational studies. Prior to joining Threshold he was Senior Director of Biology at Galileo Pharmaceuticals from 2001 to 2004, Director of Drug Discovery at Signature Bioscience from 2000 to 2001, and a Research Unit Director at Affymax (a Glaxo company) from 1990 to 2000. Charles received his A.B. in cell biology from the University of California at Berkeley in 1977, an M.S. in developmental biology from Stanford University in 1980, and a Ph.D. in molecular biology and genetics from Yale University in 1987. Charles completed a postdoctoral fellowship at the University of Strasbourg, France.
Hartmuth Kolb, PhD
Siemens Medical Solutions USA
In 1989-1991, Dr. Hartmuth C. Kolb received his PhD on the "Synthesis of the Azadirachtin Decalin FragmentF" in Organic Chemistry, Imperial College of Science, Technology and Medicine, London UK. He did postdoctoral work with K. Barry Sharpless at The Scripps Research Institute in La Jolla, CA, between 1992 and 1994. Subsequently, Hartmuth Kolb joined Ciba-Geigy (later Novartis Pharmaceuticals) to work on the development of carbohydrate mimics as Selectin antagonists. In 1997, Dr Kolb became the Chief Operating Officer and Head of Chemistry at Coelacanth Corporation, a chemistry company founded by K. Barry Sharpless. In this role, he and Dr. Sharpless developed the click chemistry approach to drug discovery. In 2002, he joined the Department of Chemistry of The Scripps Research Institute as an Associate Professor. Since November 2004, he has been working as the Vice President of Siemens MI, Biomarker Research, on the discovery and clinical development of new PET imaging biomarkers.
Giovanni Melillo, MD
Bristol-Myers Squibb
Dr. Giovanni Melillo obtained a medical doctor degree and a specialty in Medical Oncology from the University of Naples, Italy. He joined the Laboratory of Experimental Immunology of the National Cancer Institute in Frederick in 1991 as visiting scientist. In 1999 Dr. Melillo became Senior Investigator with the Developmental Therapeutics Program of the National Cancer Institute at Frederick where he has contributed to the implementation of a drug discovery and development program targeting the transcription factor Hypoxia Inducible Factor 1. Dr. Melillo is currently Medical Director, Discovery Medicine Oncology at Bristol-Myers Squibb, where he is contributing to the development of novel drugs for cancer therapy. Dr. Melillo serves as Associate Editor of Journal of Molecular Medicine and Cancer Research and is on the Editorial Board of Molecular Cancer Therapeutics, Cell Cycle, Molecular Cancer and Cell Death and Disease.
Maria V. Papadopoulou, PhD
NorthShore University HealthSystem, University of Chicago
Dr. Maria V. Papadopoulou is a Senior Research Scientist and a Research Associate Professor of the Department of Radiation Medicine at NorthShore University HealthSystem, which is affiliated with the University of Chicago. She received her PhD at the Aristotelian University of Thessaloniki in Greece, where she became Assistant Professor in the Chemistry Department. She has worked as a postdoctoral fellow in the Chemistry Departments of a) Princeton University, with Professor Edward C. Taylor, where she worked in the synthesis of antifolates (Alimta), and b) the University of Pittsburgh with Professor Andrew Hamilton, where she developed artificial, macrocyclic receptors for molecular recognition of drugs and DNA bases. Since 1990 she has worked in cancer research with Dr. William D. Bloomer, Chairman of the Dept. of Radiation Medicine at NorthShore University HealthSystem and Professor of Radiation Oncology at the University of Chicago, in the development of bioreductive compounds as hypoxia-selective cytotoxins and markers for hypoxia. In addition, she tries to develop compounds against various infectious diseases, such as Tuberculosis, American and African Trypanosomiasis, and malaria. She has published more the 55 peer reviewed articles and is a holder of 4 patents.
Sponsors
Bronze Sponsors
Threshold Pharmaceuticals
Grant Support
This conference is supported by an educational grant from Millennium Pharmaceuticals, Inc., The Takeda Oncology Company
Academy Friends
Abcam plc.
BioSpherix, Ltd.
Centella Therapeutics
HypOxygen
Ruskinn Technology Ltd.
Promotional Partners
Nature Medicine
The New York Academy of Medicine
Abstracts
A Critical Evaluation of Methods for Imaging Tumor Hypoxia
Mark W. Dewhirst, DVM, PhD, Duke University Medical Center
It has been known for nearly 60 years that hypoxia is a root cause for treatment resistance to radiotherapy, but the discovery of hypoxia inducible transcription factors in the early 1990's led to an explosion of interest in its importance in tumor biology. It is now well established that hypoxia not only is a root cause for treatment resistance to radiation and chemotherapy. It also contributes to more aggressive tumor behavior by: 1) stimulating angiogenesis, 2) altering metabolism toward glycolysis, 3) harboring sites for stem cell maintenance and 4) favoring epithelial mesenchymal transition and metastasis. Thus, there is strong rationale for identifying those tumors that harbor hypoxic tumor cells as well as identifying methods to successfully eradicate them.
There are literally dozens of methods that have been used to measure tumor hypoxia. But, to understand how to best use these methods, it is important to understand the nature of hypoxia in tumors. In this lecture, I will first review the basic principles underlying the pathophysiologic features of tumor hypoxia. Then, I will discuss how various methods can be used to evaluate features of hypoxia as well as serially monitor changes in hypoxia brought on by therapeutic intervention. The discussion will include methods that are readily available today for clinical application, as well as cutting edge technologies that may become available in the future.
Selective Targeting of Hypoxic Cancer Cells with the Hypoxia-activated Prodrug TH-302: Preclinical and Clinical Studies
Charles P. Hart, PhD, Threshold Pharmaceuticals
Hypoxic subregions are a prevalent feature of solid tumors, and have also been shown to exist in the diseased bone marrow of hematological malignancies. Tumor hypoxia is associated with poorer clinical prognosis. This is directly related to more rapid treatment failure (chemotherapy, radiotherapy) and the hypoxic induction of a more aggressive, invasive, and metastatic cancer phenotype. The low oxygen concentration in hypoxic tumor cells also allows their selective targeting via hypoxia-activated cytotoxic prodrugs (HAPs). TH-302 is a 2-nitroimidazole triggered bromo-isophosphoramide mustard that upon release causes DNA cross-linking and cell death in a hypoxia-selective manner in both human tumor cell lines in vitro and in human tumor xenografts in vivo. TH-302 was designed with a specific pharmacologic profile for an optimized HAP, including tissue penetrability, specific oxygen concentration dependence for activation, low susceptibility to metabolic inactivation and a bystander effect. TH-302 has been investigated in over 600 patients and is currently in Phase 1, Phase 2, and Phase 3 clinical trials. These include TH-302 monotherapy, combinations with conventional chemotherapeutics and combinations with molecularly targeted anti-angiogenic therapies known to induce hypoxia. Single agent activity was reported in the initial monotherapy study with tumor responses in patients with metastatic melanoma, SCLC and head and neck cancer. Development in soft tissue sarcoma is the most advanced with a randomized controlled Phase 3 trial comparing doxorubicin versus doxorubicin + TH-302 initiated in 2011. The specific contribution of TH-302 in combination therapy was demonstrated in a randomized controlled Phase 2b trial comparing gemcitabine versus gemcitabine + TH-302 in first-line advanced pancreatic cancer. The top-line results from this latter trial demonstrated a significant improvement (p=0.005, logrank test) in progression-free survival (PFS) with a median PFS of 3.6 months for patients treated with gemcitabine alone compared to 5.6 months for patients treated with gemcitabine + TH-302 groups and hazard ratio of 0.61(95% CI: 0.43 – 0.87). The response rate in the combination groups was 22% versus 12% in the gemcitabine alone group. TH-302 exhibits an attractive safety profile with TH-302 related skin and mucosal toxicities that are generally not dose limiting and associated myelosuppression that may be dose limiting in combination with cytotoxics. Taken together, the preclinical and emerging clinical results show that TH-302 can be administered safely in combination with the full dose conventional chemotherapeutics and that TH-302 as a monotherapy and in combination exhibits encouraging efficacy in a variety of solid tumors types.
Molecular Imaging of Hypoxia
Hartmuth C. Kolb, PhD, Siemens Medical Solutions, USA
Hypoxia in tumors has been shown to have a tremendous impact on cancer therapy outcomes. It is associated with decreased radiosensitivity and increasing evidence points to the ability of hypoxia to induce the expression of gene products, which confer aggressive tumor behaviors and promote broad resistance to therapy in general. Information on the tumor hypoxia status may allow response prediction and, as a consequence, enable more effective, personalized treatment. Visualization of hypoxic regions in tumors prior to initiation of therapies may be helpful in identifying patients that may benefit from alternative treatment approaches for hypoxic tumors, e.g. use of radiosensitizers, higher radiation doses, or hypoxia-selective cytotoxins. This presentation deals with recent advances in PET hypoxia imaging, based on 2-nitroimidazole agents that measure the cellular redox potential, and on CA-IX ligands that measure the cellular response to hypoxia. We will describe the preclinical validation of several hypoxia tracers, e.g. [18F]-HX4 and [18F]-VM4-037, and early-stage clinical studies.
Targeting Hypoxic Cell Signaling for Cancer Therapy
Giovanni Melillo, MD, Bristol-Myers Squibb
Low oxygen levels (hypoxia and/or anoxia) are frequently detected in human cancers and are a hallmark of the tumor microenvironment. Hypoxia profoundly affects the behavior of cancer cells by inducing a shift in tumor metabolism, increasing the production of angiogenic factors and activating pathways that mediate invasion and metastasis. Overall, a hypoxia tumor microenvironment has a negative influence on the potential efficacy of chemotherapy and radiation therapy, and is ultimately associated with poor patients’ prognosis. Conversely, intra-tumor hypoxia may represent a unique opportunity for the development of therapeutic approaches that selective target hypoxic cells, sparing normal oxygenated tissues. Hypoxia Inducible Factor 1 (HIF-1) is a master regulator of the transcriptional response to low oxygen levels. Several approaches have been pursued to develop small molecules targeting HIF-1. Although the majority of HIF-1 inhibitors identified lack specificity, evidence of target modulation associated with anti-tumor activity has been provided both in xenograft models and in early clinical trials. Combination therapies with antiangiogenic agents, thought to increase intra-tumor hypoxia, may provide a unique setting in which to exploit HIF-targeted therapies. Given the challenges associated with directly targeting HIF-1, many strategies have been proposed targeting downstream mediators of HIF transcriptional activity. Evidence will be discussed that highlight novel pathways triggered by intra-tumor by hypoxia that may represent viable targets for development of cancer therapeutics.
NLCQ-1 (NSC 709257): A Weak DNA-intercalating Bioreductive Agent — An Overview and New Prospects
Maria V. Papadopoulou, PhD, NorthShore University HealthSystem, University of Chicago
NLCQ-1 is a weak DNA-intercalating hypoxia-selective cytotoxin which interacts synergistically with radio/chemotherapy, radioimmunotherapy and Gene Directed Enzyme Prodrug Therapy (GDEPT) in vitro and in vivo, without a concomitant systemic toxicity. In addition, NLCQ-1 remarkably prevents metastasis and demonstrates anti-tuberculant activity against non proliferating TB. NLCQ-1 is almost ready to enter a phase I clinical trial as an adjuvant to radio/chemotherapy. Data of the preclinical development of NLCQ-1 will be presented.
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