The Pancreatic Cancer Action Network hosts this first Summit on Pancreatic Cancer. Leading pancreatic cancer investigators and other luminaries of the biological sciences engage in an interactive discussion of opportunities and challenges facing pancreatic cancer research over the next five years.
Cancer Stem CellsAugust 3, 2007
Speakers: Diane Simeone, Geoff Wahl, Susan Bonner-Weir
Run Time: 2 hours 14 minutes
Cell of OriginAugust 3, 2007
Speakers: Steven Leach, Sunil Hingorani
Run Time: 1 hours 25 minutes
Signaling and Mechanism Based Therapeutic StrategiesAugust 3, 2007
Speakers: Tony Hunter, Neal Rosen, Channing Der, Murray Korc
Run Time: 1 hours 24 minutes
Ex Vivo and In Vivo ModelingAugust 3, 2007
Speakers: Dafna Bar-Sagi, David Tuveson, Nabeel Bardeesy
Run Time: 1 hours 17 minutes
Oncogenesis and InflammationAugust 4, 2007
Speakers: Mariano Barbacid, Inder Verma, Ashok Saluja
Run Time: 1 hours 45 minutes
The Crossroads of Inflammation and MetabolismAugust 4, 2007
Speakers: Ronald Evans, Reuben Shaw, Michael Karin
Run Time: 1 hours 10 minutes
Exploiting Molecular Tools to Personalize Pancreatic Cancer TherapeuticsAugust 4, 2007
Speakers: Timothy Yeatman, Mace Rothenberg
Run Time: 1 hours 22 minutes
Hunting for and Using Pancreatic Cancer GenesAugust 4, 2007
Speakers: Ralph Hruban, David Tuveson
Run Time: 2 hours 42 minutes
Early Detection and Translational ResearchAugust 5, 2007
Run Time: 1 hours 33 minutes
Therapeutics and Clinical ImplicationsAugust 5, 2007
Run Time: 1 hours 21 minutes
Friday, August 3, 2007
Saturday, August 4, 2007
Sunday, August 5, 2007
Diane M. Simeone, MD, University of Michigan, Ann Arbor, MI
Dr. Simeone is the principal director of a research laboratory that is funded by the National Institutes of Health. Her basic science laboratory investigates mechanisms of pancreatic growth regulation and molecular events important in the development and progression of pancreatic adenocarcinoma. She is also an associate member of the Early Detection Research Network (EDRN), an NCI-funded initiative to identify and validate early detection biomarkers for the diagnosis of pancreatic cancer.
Geoffrey M. Wahl, PhD, Salk Institute, La Jolla, CA
Dr. Wahl is a professor in the Gene Expression Laboratory studying the genetic basis of the origin and progression of cancer and why tumors become resistant to drugs. The underlying mechanisms of the genetic instability of cancer cells, and of their ability to develop resistance to anti-cancer drugs have remained a mystery to cancer biologists for the better part of a century. Wahl has found evidence that the instability derives from mutations in key genes that determine when it is safe for the cell to begin the important process of duplication of the genetic material. Such mutations also prevent cancer cells from responding to treatments commonly used in therapy that produce DNA damage, such as ionizing radiation. This increases the chances that a mutant cell will be produced every time it tries to reproduce itself. While this gives cancer cells many advantages for growth under stressful conditions, it also provides novel routes for the development of new anti-cancer therapies. The lab is now investigating how p53 is regulated, as 50% of human cancers express wild type p53 that is functionally compromised. Their efforts center on the use of in vitro systems and genetically modified mice to understand the contributions of two related proteins, Mdm2 and Mdm4 (Mdmx) to p53 regulation. Previous studies have shown that these proteins are essential for controlling p53 activity, and that they are frequently over-expressed in cancer cells as a way to mitigate p53 function in tumors containing wild type p53 genes. A goal of these studies is to develop drugs that antagonize Mdm2 and Mdmx to treat patients when tumors over-express these proteins. Another area of investigation concerns the identification and isolation of stem cells that are required to form each of the different types of cells in organs such as the mammary gland. This is important as the special properties of such cells, including their abilities to self-renew and to divide infrequently may enable them to contribute to cancer formation and to drug resistance.
Susan Bonner-Weir, PhD, Joslin Diabetes Center, Harvard Medical School, Boston, MA
Dr. Bonner-Weir and her colleagues believe that a better understanding of the regulation of pancreatic growth and differentiation may lead to new therapies, including generation of new beta cells and amplification of beta cells from the pancreas (either human or animal) to be used for transplantation. Her research has focused on the endocrine pancreas (the islets of Langerhans) in three areas: 1) the architecture of the islet and its implications for function; 2) the in vivo regulation of beta-cell mass; and 3) the factors involved in islet growth and differentiation.
With a series of rodent models they have provided compelling evidence that adult pancreatic beta-cell mass increases in response to a metabolic need and have been examining the mechanisms of this postnatal pancreatic growth. In the adult rat after partial pancreatectomy, massive regeneration occurs with both enhanced replication of preexisting beta cells and ductal expansion and subsequent differentiation into endocrine, exocrine or mature duct cells. They are defining the cells that are involved and the factors that are carefully orchestrated in vivo to stimulate the growth and differentiation of the beta cells. Another project is to define markers of newly formed beta cells. Additionally they have been successful in vitro cultivation of human islets from pancreatic ductal cells and are characterizing the cells that give rise to the new islets. Their overall hypothesis has been that in the adult pancreas duct cells act as pancreatic progenitors, such that with replication the mature duct cell regresses to a less differentiated cell (perhaps equivalent to a embryonic pancreatic duct cell) and regains its potential to differentiate into islet, acinar or mature duct cell, and that this phenotypic differentiation is directed by external signals or morphogens. Using the Cre-lox system for lineage tracing they are showing that in growth after birth and injury that mature duct cells serve as the progenitor for new islets and new acini.
Steven Leach, MD, Johns Hopkins University, Baltimore, MD
Dr. Leach studies epithelial differentiation in exocrine pancreas, using both mouse and zebrafish model systems. This work is guided by the principle that pancreatic cancer may be initiated by changes in epithelial differentiation involving reprogramming of pancreatic progenitor cells. Our recent work has demonstrated that exocrine progenitor cells in adult and embryonic pancreas are regulated by specific interactions between the Notch and EGF signaling pathways, and that these interactions may be involved in the initiation of human pancreatic cancer. Current areas of emphasis include: 1) Evaluation of musashi RNA binding proteins in the regulation of pancreatic progenitor cells; 2) Identification of novel transcription factors regulating pancreatic epithelial differentiation; 3) Generating a zebrafish pancreatic cancer model amenable to high-throughput small molecule screens; 4) Application of transposon technology for large-scale mutagenesis of the zebrafish genome.
Sunil Hingorani, MD, PhD, Fred Hutchinson Cancer Institute, Seattle, WA
Dr. Hingorani focuses his laboratory on the use of genetically engineered mouse models to answer fundamental questions about the biology of pancreas cancer. By directing the expression of key mutations in specific oncogenes and tumor suppressor genes to the mouse pancreas, we have developed models that faithfully mimic the spectrum of human pancreatic ductal adenocarcinoma (PDA) from its earliest preinvasive lesions to locally invasive and widely metastatic disease. Our goals are to use these models to reveal basic mechanisms of disease pathogenesis, as well as to serve as platforms for the design and testing of strategies for early detection and for treatment and chemoprevention.
Three broad areas of inquiry are currently being pursued: 1) continuing investigations into the molecular requirements for disease progression and their respective impact on the resultant clinical and biological phenotype; 2) investigations into the cell-of-origin for preinvasive and invasive ductal carcinoma and the possibility that it may represent a mutated tissue progenitor cell; 3) efforts to identify biomarkers of early disease and markers associated with disease response and resistance to therapy.
Neal Rosen, MD, PhD, Memorial Sloan Kettering, New York, NY
Dr. Rosen focuses his laboratory on the identification and characterization of signal transduction pathways that cause the dysregulation of growth and inhibition of apoptosis that characterize advanced human cancer. Our laboratory is dedicated to understanding the consequences of activation of these pathways and to using this information to develop mechanism-based therapeutic strategies. A major focus is the evaluation of Hsp90 as a therapeutic target in cancer patients. Hsp90 is a cellular chaperone that is required for maintaining the proper conformation of several important signaling proteins, including transmembrane tyrosine kinases and steroid receptors. The laboratory is studying the role of Hsp90 family members in maintaining the transformed phenotype of cancer cells. The knowledge gained is being used to develop strategies for using Hsp90 inhibitors in patients. A lead compound, the ansamycin 17-AAG, is currently in clinical trial at MSKCC. The laboratory has developed, and is currently evaluating, second generation ansamycins and small-molecule inhibitors with potentially greater selectivity and more favorable pharmacologic properties. (See ansamycin and small-molecule inhibitor projects.)
In addition, the laboratory is studying kinase inhibitors that target EGFR, HER2, MEK, src, mTOR, Met, and small molecules that inhibit androgen receptor and estrogen receptor. These compounds are being used as re-agents to define the role of these pathways in tumor cells with the goal of developing strategies for using these agents in patients.
Channing J. Der, PhD, University of North Carolina, Chapel Hill, NC
Dr. Derâ€™s research focuses on understanding the molecular basis of human carcinogenesis. Specifically, their research studies have dealt with three distinct aspects of Ras family oncogene proteins and on the discovery of novel oncogenes involved in specific human cancers. First, we are interested in complex nature of signal transduction pathways that mediate the oncogenic actions of Ras. Ras is mutationally activated in 30% of all human cancers, with high frequencies seen in lung, colon, and pancreatic cancers. It has become apparent that Ras regulates a multitude of signaling pathways via its interaction with a surprisingly diverse spectrum of downstream effector targets, which include the Raf serine/threonine kinase and the Tiam1 activator of Rac. To date, at least a dozen distinct Ras effector targets have been identified and we are interested in how each contributes to oncogenic Ras deregulation of gene expression and promotion of tumor cell invasion and metastasis.
Second, we now know that the three Ras proteins represent only a mere subset of a large superfamily of Ras-related proteins. Mammalian members of this family number more than 100, with more likely to be discovered. Since Ras-related proteins share strong sequence and biochemical similarities with Ras proteins, a logical question is whether the aberrant function of any other members of this superfamily are also oncogene proteins involved in cancer development. Much of our current interest has centered on members of the Rho family of Ras-related proteins, which function as regulators of a wide spectrum of cellular processes that include actin cytoskeletal organization, gene expression and cell cycle progression. How Rho proteins contribute to Ras transformation, and what signaling pathways connect Ras with Rho, are questions that we are pursuing in our studies. Another class of Ras superfamily proteins appears to function as tumor suppressors, rather than oncogenes. Understanding why these proteins share significant biochemical properties with Ras, yet inhibit tumor progression, is a goal of our studies.
Third, we are involved in drug discovery efforts to target Ras for cancer treatment. For example, our studies involve evaluating the ability of inhibitors of Ras signaling (e.g., Raf and MEK kinase inhibitors) to block the growth of Ras mutation positive human cancers. Finally, we have developed biological screens to search for novel oncogenes that are activated in a variety of human cancers, including carcinomas of the breast, colon, prostate and pancreas. In summary, our studies span the broad range from gene discovery to drug discovery, with the long range goal of identifying better diagnostic and therapeutic approaches for cancer treatment.
Murray Korc, PhD, Norris Cotton Cancer Center, Dartmouth, NH
Dr. Korc is interested in the molecular biology of pancreatic cancer; mechanisms of action of peptide hormones and growth factors; abnormal gain of function through negative pathways; resistance of cancer cells to apoptosis; tumor angiogenesis. Most of the work in Dr. Korc's laboratory explores aberrant signaling pathways in cancer cells. Studies include signaling by the epidermal growth factor (EGF) receptor, fibroblast growth factor (FGF) receptors, transforming growth factor beta (TGF-b) receptors and vascular endothelial cell growth factor (VEGF) receptors. The potential role of co- receptors such as glypican-1 and neuropilins are also being actively investigated. The model system that is most often studied is pancreatic cancer. The overall hypothesis guiding the studies of pancreatic cancer is that superimposed on alterations in oncogene and tumor suppressor gene functions, there is evidence for excessive mitogenic signaling, loss of negative growth constraints, and abnormal gain of function through negative signaling pathways, through suppression of differentiation, through excessive resistance to apoptosis, and through aberrant angiogenesis. Knowledge gained from these studies is being used to devise novel therapeutic strategies for this deadly disease.
David Tuveson, MD, PhD, Cambridge Research Institute, Cambridge, England
Dr. Tuveson is interested in Tumour Modeling & Experimental Medicine (Pancreatic Cancer). His research interests involve pancreatic cancer and melanoma---deadly malignancies when detected at late stages. His laboratory investigates both of these cancers by producing models in Mus musculus that mimic the human diseases closely, and participating in clinical trials with experimental therapeutics. The goals of the laboratory are to identify the essential components of malignant transformation of pancreatic cells and melanocytes in vivo, and to translate this knowledge into effective tumour detection and treatment strategies.
Dafna Bar-Sagi, PhD, New York University, New York, NY
Dr. Bar-Sagi directs research to understand the processes of life at the biochemical level. Her research includes studies on the molecular mechanisms and regulation of RNA and DNA synthesis, recombination, oxygen sensing and signaling, mechanisms of nitric oxide action, mechanisms of chaperone-assisted protein folding, protein structure, stress signaling and response, mechanisms of G-protein function, HIV prophylaxis, neuron receptor localization and signaling mechanisms that determine the spatial directions of neuron motility.
Michael Goggins, MD, Johns Hopkins University School of Medicine, Baltimore, MD
Dr. Gogginsâ€™ research interests include the molecular genetics of pancreas cancer, particularly the role of germline BRCA2 mutations in pancreas cancer and characterizing the molecular genetic progression model for pancreas cancer.
Timothy Yeatman, MD, Moffitt Cancer Center, Tampa, FL
Dr. Yeatman has focused his research on the management of gastrointestinal malignancies with a special research emphasis on using genome scale microarrays to identify the molecular signatures of cancer that provide diagnosis, prognosis and response to therapy. Dr. Yeatman recently compared microarray data of 540 human tumors of 21 different tumor types with the diagnoses obtained from tumor biopsies. He found that microarray was 88 percent accurate in predicting all tumor types. The results of his investigation, the first such work to be reported in this depth, appeared in the January 2004 issue of the American Journal of Pathology. In addition, he and his colleagues have detected 340 new tumor markers and more than 100 tumor progression markers whose expression correlated with progressing tumor stage. Some of these markers may be useful in the clinical management of colon cancer patients because of their capacity to detect and predict the stage of cancer.
Mace Rothenberg, MD, Vanderbilt University, Nashville, TN
Dr. Rothenberg is a medical oncologist who specializes in Phase I drug development and clinical trial design with an emphasis in gastrointestinal cancers (particularly colorectal and pancreatic). His research focuses on evaluating new drugs in humans from a clinical, pharmacological, biological and genetic perspective. He studies novel cancer therapeutic agents to determine their safety and clinical application, and his most significant contributions have been in the development and FDA approval of drug treatments for colorectal and pancreatic cancer.
Dr. Rothenberg is recognized nationally and internationally as an expert on clinical trial design and evaluating new treatments. Vanderbilt is one of only 16 institutions designated and funded by the National Cancer Institute (NCI) as a Phase I Center. Several of Dr. Rothenberg's studies focus on investigational drugs for patients with advanced cancers for which there is no known effective or curative therapy. He is recognized nationally and internationally for his work, serves on a number of advisory committees, and is an editorial board member for numerous publications including Clinical Cancer Research, Clinical Colorectal Cancer and Investigational New Drugs, and The Journal of New Anticancer Agents.
Ralph Hruban, MD, Johns Hopkins University School of Medicine, Baltimore, MD
Dr. Hruban received his Doctor of Medicine from The Johns Hopkins University. He continued at Johns Hopkins for his residency training, spent one year as a Fellow at Memorial Sloan-Kettering Cancer Center in New York and then returned to Johns Hopkins to join the Faculty in 1990. He established the National Familial Tumor Registry January 1, 1994.
Dr. Hruban is currently Director of The Sol Goldman Pancreatic Cancer Research Center and Director of the Division of Gastrointestinal/Liver Pathology. Dr. Hruban has written over 400 scientific papers, 80 book chapters and reviews, and three books. He is recognized by the Institute for Scientific Information as a Highly Cited Researcher and by Essential Science Indicators as the most highly cited pancreatic cancer scientist - designations given to the most highly influential scientists. In addition to his research efforts, he helped create the Johns Hopkins Pancreatic Cancer Web Page, http://pathology.jhu.edu/pancreas. Dr. Hruban has received a number of awards including the Arthur Purdy Stout Prize for significant career achievements in surgical pathology, the Young Investigator Award from the United States and Canadian Academy of Pathology, the Pancreatic Cancer Action Network Medical Visionary Award, and five teaching awards from Johns Hopkins School of Medicine. Dr. Hruban is a member of the Scientific Advisory Board of the Pancreatic Cancer Action Network, The Joseph C. Monastra Foundation and The Michael Rolfe Pancreatic Cancer Foundation, and the Director of Science for The Lustgarten Foundation.