
Targeting Key Vulnerabilities in Pancreatic Cancer
Thursday, October 9, 2014
Pancreatic ductal adenocarcinoma remains one of the most challenging problems in oncology, with a 5-year survival rate of just 6% and few effective therapeutic options. Genomic studies have identified only four high penetrance mutations responsible for the initiation and progression of pancreatic cancer. Unfortunately, none of these alterations can currently be targeted therapeutically. Nonetheless, core signaling programs are beginning to be identified for which therapeutic approaches may be developed. Some of these programs constitute “critical dependencies” of the tumor — biological pathways on which the tumor relies for continued growth and survival — and may serve as effective therapeutic targets. These programs include metabolic alterations that take place in pancreatic tumor cells, the behavior and biology of the tumor stroma, and interactions with the host immune system. This symposium will focus on recent breakthroughs in the pathogenesis and progression of pancreatic cancer, and efforts to exploit these key vulnerabilities as the basis for novel therapeutic interventions.
*Reception to follow.
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Agenda
* Presentation titles and times are subject to change.
October 9, 2014 | |
8:00 AM | Registration and Continental Breakfast |
8:30 AM | Welcome and Introductory Remarks |
8:45 AM | Morning Keynote Presentation Ending the Beginning: Targeting PanIN Initiation and ProgressionSteven D. Leach, MD, Memorial Sloan Kettering Cancer Center |
9:30 AM | Modulation of the Pancreatic Tumor Microenvironment by SBRT and Cell Death |
10:00 AM | Networking Coffee Break |
10:30 AM | Translational Efforts Towards the Imaging and Treatment of Pancreatic Cancer |
11:00 AM | Macrophages — Master Regulators of the Immune Reaction to Pancreatic Cancer |
11:30 PM | Late-Breaking Abstract Presentation 1 Exploiting Glutamine Addiction in Pancreatic Cancer Costas A. Lyssiotis, PhD, Weill Cornell Medical College |
11:45 AM | Late-Breaking Abstract Presentation 2 Control of Stress Granules by Oncogenic KRas Drives Tumor Drug Resistance in PDAC |
12:00 PM | Networking Lunch and Poster Session All Poster Presenters are requested to be present at their posters between 12:20 PM - 12:50 PM |
1:00 PM | Imaging Pancreatic Cancer and its Microenvironment in Living Mice |
1:45 PM | T-cell Exclusion in Pancreatic Ductal Adenocarcinoma: The Cancer-associated Fibroblast Expressing Fibroblast Activation Protein and CXCL12 |
2:15 PM | Networking Coffee Break |
2:45 PM | Afternoon Keynote Presentation Hypoxia and Precision Medicine in Pancreatic Adenocarcinoma (PDAC): Defining the Target before Targeting the Therapy |
3:30 PM | Late-Breaking Abstract Presentation 3 Enzymatic Remodeling of the Pancreatic Ductal Adenocarcinoma Tumor Microenvironment to Improve Chemotherapeutic Efficacy |
3:45 PM | Closing Remarks |
4:00 PM | Networking Reception |
5:00 PM | Adjourn |
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.
George B. Zavoico, PhD
MLV & Co.
Jennifer S. Henry, PhD
The New York Academy of Sciences
Keynote Speakers
Neesha Dhani, MD, FRCPC
Princess Margaret Hospital, Toronto
Dr. Neesha Dhani completed her undergraduate medical training at the University of Western Ontario, subsequently pursuing internal medicine and medical oncology subspecialty training at the University of Toronto. She then pursued a translational research fellowship at the Princess Margaret Cancer Center, combining training in clinical research through the Drug Development Program with basic and translational research towards a PhD focusing on hypoxia related invasion and metastasis in pancreatic cancer. She is now a staff medical oncologist at the Princess Margaret Cancer Center in Toronto Ontario with a clinical focus in the management of patients with GI (pancreatic, biliary, HCC) and gynecologic cancers. Her on-going research includes developing and evaluating novel techniques of functional imaging for characterization of the tumoral microenvironment with a goal of improving drug development in this area.
Steven D. Leach, MD
Memorial Sloan Kettering Cancer Center
Steven D. Leach is the inaugural Director the David Rubenstein Center for Pancreatic Cancer Research at Memorial Sloan Kettering Cancer Center (MSKCC). He is also a member of the Human Oncology and Pathogenesis Program (HOPP). Prior to this he served as the Paul K. Neumann Professor in Pancreatic Cancer at Johns Hopkins, where he was also Professor of Surgery, Oncology and Cell Biology. Dr. Leach received his bachelor’s degree with high honors in Biology from Princeton University, where he currently serves as a member of the Board of Trustees. This was followed by medical school at Emory University, where he was a Robert W. Woodruff Scholar. Dr. Leach then pursued residency training in General Surgery at Yale University, where he also completed a two-year research fellowship studying acinar cell biology in the laboratory of Fred Gorelick. Following an additional fellowship in Surgical Oncology at M.D. Anderson, he joined the faculty at Vanderbilt University, first as an Assistant Professor and then as Associate Professor of Surgery and Cell Biology. In 2000, he moved to Johns Hopkins to become the first Paul K. Neumann Professor, and moved to MSKCC in 2014. Dr. Leach’s lab has a long track record of research productivity in the field of pancreatic cancer biology. His lab is credited with discovery of abnormal Notch pathway activation as an important driver of pancreatic tumorigenesis, development of the first zebrafish model of pancreatic cancer, identification of adult acinar cells as effective cells of origin for the initiation of pancreatic “ductal” neoplasia, and the recent identification of a hematopoietic-to-epithelial IL-17 signaling axis required for PanIN initiation. Together with his group’s additional studies of pancreatic developmental biology and pancreatic epithelial plasticity, Dr. Leach’s work has contributed significantly to our understanding of early pancreatic cancer.
Speakers
Gregory Beatty, MD, PhD
University of Pennsylvania Perelman School of Medicine
Gregory Beatty, MD, PhD is an Assistant Professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania and in the Division of Hematology/Oncology within the Abramson Cancer Center at the Hospital of the University of Pennsylvania. Dr. Beatty graduated from Bucknell University and received his PhD in Immunology followed by an MD from the University of Pennsylvania Perelman School of Medicine. He went on to complete a residency in Internal Medicine and a fellowship in Medical Oncology at the Hospital of the University of Pennsylvania. Dr. Beatty's research interest is in understanding the role of macrophages in regulating innate and adaptive immunosurveillance in cancer. He has developed a research platform within his laboratory that uses genetically engineered mouse models of cancer to study leukocyte biology within the tumor microenvironment and to screen novel immunotherapeutic strategies, including cell and gene therapies, for the treatment of cancer. In addition, he is currently leading the clinical investigation of T cell adoptive therapies and other immunotherapeutic approaches for pancreatic cancer.
Mikala Egeblad, PhD
Cold Spring Harbor Laboratory
Mikala Egeblad obtained degrees in Medicine (B.S., 1993), Human Biology (M.Sc., 1996), and Cancer Biology (Ph.D., 2000) from the University of Copenhagen, Denmark. In 2001, Mikala Egeblad joined Dr. Zena Werb’s lab at University of California, San Francisco as a postdoctoral fellow. There, she began employing mouse models to understand how the microenvironment influences tumor progression, focusing on innate immune cell responses and protease-mediated extracellular matrix remodeling. With Zena Werb and postdoctoral fellow Dr. Andrew Ewald, she also developed methods for using spinning disk confocal microscopy to image tumor-stroma interactions in breast cancer. In 2009, she came to Cold Spring Harbor Laboratory as an Assistant Professor and in 2014; she was promoted to Associate Professor. For her research in breast cancer, she was in 2014 awarded the Era of Hope Scholar Award from the Department of Defense, Congressionally Directed Medical Research Programs.
Douglas T. Fearon, MD
Weill Cornell Medical College and Cold Spring Harbor Laboratory
Douglas Fearon received his MD from Johns Hopkins Medical School and completed his internal medicine training on the Osler Medical Service of the Johns Hopkins Hospital. After serving as a physician in the Army, he was a post-doctoral fellow in rheumatology at Harvard Medical School. He continued at that institution and was appointed Professor of Medicine in 1984. He moved back to Johns Hopkins in 1987 as Professor of Medicine and as Director of the Division of Molecular Rheumatology, and of the Graduate Program in Immunology. In 1993, he moved to the University of Cambridge as a Wellcome Trust Principal Research Fellow. He was elected a Fellow of Trinity College in 2001, and as the Sheila Joan Smith Professor of Immunology in 2003. He recently returned to the United States as the Walter B. Wriston Professor of Pancreatic Cancer Research at Weill Cornell Medical College, and as a Professor at Cold Spring Harbor Laboratory. He is a Fellow of the Royal Society, a member of the National Academy of Sciences, a Fellow of the American Academy of Arts and Sciences, and a Fellow of the Academy of Medical Sciences. His recent research has focused on cancer immunology.
Elda Grabocka, PhD
Department of Biochemistry and Molecular Pharmacology, NYU Langone School of Medicine, New York, NY
Dr. Grabocka completed her undergraduate studies in Biology at Washington College. She received her PhD degree in Molecular Pharmacology and Structural Biology at Thomas Jefferson University and is currently a postdoctoral fellow in the laboratory of Dafna Bar-Sagi, PhD at NYU Langone Medical Center. Dr. Grabocka’s research is centered on elucidating dependencies of oncogenic KRAS cancers on tumorigenic stress adaptation mechanisms, and their integration in therapeutic intervention modalities.
Costas A. Lyssiotis, PhD
Weill Cornell Medical College
Dr. Costas A. Lyssiotis obtained his bachelor’s degree in chemistry and biochemistry from the University of Michigan and his PhD in chemical biology at The Scripps Research Institute in La Jolla, CA. In 2010, he joined the laboratory of Prof. Lewis C. Cantley at Harvard Medical School as the Amgen fellow of the Damon Runyon Cancer Research Foundation. He is currently a Pancreatic Cancer Action Network Pathway to Leadership Postdoctoral Fellow in Prof. Cantley’s laboratory, now at Weill Cornell Medical College. His research is focused on understanding the biochemical pathways and metabolic requirements that enable pancreatic tumor growth and, in particular, how this information can be used to design targeted therapies to treat this dreadful disease. Among his many contributions, he demonstrated that pancreatic cancers are addicted to glucose and glutamine and use these nutrients in previously undescribed pathways to make DNA and to generate free radical-combating antioxidants, respectively. For this work, he was recently awarded a Dale F. Frey Award for Breakthrough Scientists.
George Miller, MD
NYU Langone Medical Center
Dr. Miller is Associate Professor at NYU School of Medicine with appointments in the Departments of Surgery and Cell Biology where he has been on faculty for 7 years. He is Vice-Chairman for Research in the Surgery Department and co-leader of the Multidisciplinary Gastrointestinal Cancer Program. Dr. Miller’s lab is studying inflammation and the inflammation-cancer paradigm within the liver and pancreas. They are interested in numerous aspects of the biology of the pancreatic tumor microenvironment and its influence on epithelial mutagenesis. Their recent investigations have examined the role of novel pattern recognition receptors, intra-tumoral dendritic cells, and novel T cell subpopulations. They have also examined the role of chemokines and signaling molecules in mediating epithelial-stromal crosstalk. Their research in liver inflammation has focused on the role of antigen-presenting cells and novel innate cellular subsets and signaling receptors in mediating acute liver injury and chronic liver inflammation leading to fibrosis and carcinoma. Dr. Miller is a summa cum laude graduate of Columbia College and obtained his MD from McGill University Faculty of Medicine. He completed his clinical and research training at NYU and Memorial Sloan Kettering Cancer Center. His lab is supported by grants from the National Cancer Institute, the National Institute of Diabetes and Digestive Diseases, the US Department of Defense, and numerous foundations.
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.
Curtis B. Thompson, PhD
Halozyme Therapeutics, Inc., San Diego, CA
Dr. Thompson has over 15 years of preclinical experience in the pharmaceutical industry across a broad range of research disciplines, including: hypertension and vascular biology, antisense technology (ssDNA, RNAi), inflammation, osteoporosis and osteoarthritis, asthma and cancer. Curt currently is Senior Director of Pharmacology at Halozyme Therapeutics, Inc, in San Diego, California. His group is responsible for the final design of internal / external experiments in pharmacology supporting the development of new biologics.
Sponsors
For sponsorship opportunities please contact Perri Wisotsky at pwisotsky@nyas.org or 212.298.8642.
Grant Support
Supported by a grant from Genentech.
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Abstracts
Keynote Presentation
Steven D. Leach, MD, Memorial Sloan Kettering Cancer Center
Hypoxia & Precision Medicine in Pancreatic Adenocarcinoma (PDAC): Defining the Target before Targeting the Therapy
Neesha C. Dhani1
We have developed a translational program to explore the clinical relevance of hypoxia across the spectrum of PDAC. Histology-based analyses and functional imaging using nitroimidazole markers identify tissue at p02 < 10mmHg, allowing for evaluation of severe hypoxia and its biological consequences. Patient-derived xenograft (PDX) models are used to explore the efficacy of hypoxia-directed therapeutic strategies.
Resected tumours from patients receiving pre-operative pimonidazole demonstrated a range of hypoxia (hypoxic percentage (HP): 0 to 26%) in both stromal and epithelial compartments. There was significant heterogeneity within and across tumours and a small number (3 of 10 tumours) demonstrated minimal to no measureable pimonidazole. Similar trends were noted with [18F] FAZA-PET imaging of patients with advanced disease, with 5 of 20 patients demonstrating no significant hypoxia. These clinical observations are consistent with those made in PDX models where 6 of 16 demonstrated minimal hypoxia by EF5. The more hypoxic PDX models also had faster growth rates with a predilection for distant metastases. Further, these models demonstrated greater sensitivity to hypoxia targeting therapy with TH-302. This data suggests that nitroimidazole hypoxia markers are able to differentiate amongst PDAC with different levels of hypoxia. This has implications for the further development of hypoxia-targeting therapies in PDAC.
Coauthors: Cristiane Metran-Nascente1, Stefano Serra2, Ines Lohes1, Melania Pintilie3, Ivan Yeung4, Ines Lohes1, Trevor McKee4, Michael Milosevic4, Steven Gallinger5, Ming-Sound Tsao2, Richard Hill4, David Hedley1
1. Division of Medical Oncology & Hematology
2. Department of Laboratory Medicine & Pathobiology
3. Department of Biostatistics
4. Radiation Medicine Program
5. Division of Hepato-biliary Pancreatic Surgical Oncology, University Health Network and Mount Sinai Hospital
University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Ave, Toronto ON M5G 2M9
Macrophages — Master Regulators of the Immune Reaction to Pancreatic Cancer
Gregory L. Beatty, MD PhD, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
Imaging Pancreatic Cancer and its Microenvironment in Living Mice
Mikala Egeblad, PhD, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
Cross-linking and linearization of type I collagen by lysyl oxidases (LOXs) is inversely correlated with metastasis-free survival in breast cancer. We examined whether inhibiting the LOXs could limit pancreatic cancer progression. LOX and LOX-like 2 (LOXL2) were expressed at higher levels in tumors than in normal pancreatic tissue. However, inhibition of LOX activity, using a small molecule inhibitor (β-aminoproprionitirile [BAPN]) or RNA interference against either LOX or LOXL2, significantly increased tumor size and metastasis. Using live imaging, we found that LOX inhibition increased the thickness of the collagen fibers in the tumors. LOX inhibition also altered the activities of signaling molecules downstream of integrins, with more cancer cells staining positive for active focal adhesion kinase.
In conclusion, our data strongly suggest that targeting collagen cross-linking enzymes would be a poor strategy for the treatment of pancreatic cancer.
Coauthors: Mario Shields1, Pascal Maguin1, Priyanka Kumar1, Sarah L. Dallas2
1. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
2. University of Missouri, Kansas City, Missouri
Control of Stress Granules by Oncogenic KRas Drives Tumor Drug Resistance in PDAC
Elda Grabocka, PhD1
Coauthors: Yuliya Pylayeva-Gupta, PhD1, Cosimo Commisso, PhD1, Dafna Bar-Sagi, PhD1
1. Department of Biochemistry and Molecular Pharmacology, NYU Langone School of Medicine, New York, NY
Exploiting Glutamine Addiction in Pancreatic Cancer
Costas A Lyssiotis, PhD, Cancer Center, Weill Cornell Medical College, New York, New York
Modulation of the Pancreatic Tumor Microenvironment by SBRT and Cell Death
George Miller, MD, New York University School of Medicine, New York, New York, United States
Coauthors: Lena Tomkötter, Susanna Nguy, Elliot Levie, Rocky Barilla, Andrew Eisenthal, Matthew Pergamo, Nina Avanzi, Atsuo Ochi, Donnele Daley, Alejandro Torres-Hernandez, Mauricio Rendon, Sara Alothman, Dalia Qunaibit, Daniel Tippens, Mridul Pansari, Atif Salyana, Kevin Du
New York University School of Medicine, New York, New York, United States
Targeting the Inflammatory Aspect of Pancreatic Cancer through PI3Kδ Inhibition
Michael O. Ports1
Coauthors: Maryam Jangani2a, Essam Ghazaly2b, Juliana Candido2a, Jun Wang2c, Ai Nagano2c, Andrew Campbell3, Terry Gentzler1, Adam Kashishian1, Owen Sansom3, Nicholas R Lemoine2c, Christophe Quéva1, Thorsten Hagemann2a
1. Gilead Sciences, Seattle, WA 98102, USA
2. Centre for Cancer and Inflammationa, Centre for Hemato-Oncologyb, Centre for Molecular Oncologyc, Barts Cancer Institute - a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, United Kingdom
3. Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, Scotland
Enzymatic Remodeling of the Pancreatic Ductal Adenocarcinoma Tumor Microenvironment to Improve Chemotherapeutic Efficacy
Curtis B. Thompson, PhD1
Coauthors: H. Michael Shepard, PhD1 and Daniel C. Maneval, PhD1
1. Halozyme Therapeutics, Inc., San Diego, CA
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