Pancreatic ductal adenocarcinoma (PDAC) is among the leading causes of cancer death, with nearly all cases following a rapid and merciless course of intractable pain, cachexia, hopelessness and death. Repeated cycles of clinical trial failures have underscored the need for an improved understanding of PDAC pathogenesis, motivating the formation of this multi-disciplinary team of basic, translational and clinical scientists, with knowledge in cancer cell signaling, developmental and stem cell biology, tumor biology and angiogenesis, mouse models of cancer, genomics and informatics, molecular imaging, experimental pathology, and small molecule chemistry and biotherapeutics. The goal of this P01 is to further elucidate the genetics and biology of the disease to a level that will guide the rational development of effective targeted agents, alone and in combination. Specifically, we seek to (i) refine mouse models of human PDAC in order to understand the tumor biological role of PDAC signature mutations, (ii) identify, validate and characterize new human PDAC oncogenes in order to set the stage for drug discovery, (iii) illuminate and validate the role of the PI3K pathway in PDAC using mouse and human systems with the goal of identifying key therapeutic targets and guiding clinical trials targeting this pathway, (iv) utilize genetically engineered mice and human tumors to define signaling events governing the evolution and maintenance of the PDAC microenvironment, and to use this information to design and conduct innovative preclinical trials in refined mouse models of human PDAC, (v) determine the PDAC cell of origin and its genetic events in the mouse so as to illuminate a possible path to chemoprevention, and (vi) identify and characterize PDAC cancer stem cells in murine and human tumors. State-of-the-art imaging and antibody technologies, as well as strong experimental pathology and biospecimens repositories, will enable in-depth and dynamic analyses of PDAC tumor biology and signaling in unprecedented detail. The long-term goal of these basic and preclinical efforts, employing and integrating both mouse and human systems, is to identify and guide opportunities for targeted drug discovery and for the development of diagnostic agents and biomarkers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA117969-02
Application #
7223402
Study Section
Subcommittee G - Education (NCI)
Program Officer
Mohla, Suresh
Project Start
2006-04-15
Project End
2010-12-31
Budget Start
2007-01-25
Budget End
2007-12-31
Support Year
2
Fiscal Year
2007
Total Cost
$1,770,854
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Lundquist, Mark R; Goncalves, Marcus D; Loughran, Ryan M et al. (2018) Phosphatidylinositol-5-Phosphate 4-Kinases Regulate Cellular Lipid Metabolism By Facilitating Autophagy. Mol Cell 70:531-544.e9
Hopkins, Benjamin D; Pauli, Chantal; Du, Xing et al. (2018) Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560:499-503
Biancur, Douglas E; Kimmelman, Alec C (2018) The plasticity of pancreatic cancer metabolism in tumor progression and therapeutic resistance. Biochim Biophys Acta Rev Cancer 1870:67-75
Chen, Yang; LeBleu, Valerie S; Carstens, Julienne L et al. (2018) Dual reporter genetic mouse models of pancreatic cancer identify an epithelial-to-mesenchymal transition-independent metastasis program. EMBO Mol Med 10:
Hill, Margaret A; Alexander, William B; Guo, Bing et al. (2018) Kras and Tp53 Mutations Cause Cholangiocyte- and Hepatocyte-Derived Cholangiocarcinoma. Cancer Res 78:4445-4451
Mendt, Mayela; Kamerkar, Sushrut; Sugimoto, Hikaru et al. (2018) Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight 3:
Patra, Krushna C; Kato, Yasutaka; Mizukami, Yusuke et al. (2018) Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism. Nat Cell Biol 20:811-822
Anglin, Justin; Zavareh, Reza Beheshti; Sander, Philipp N et al. (2018) Discovery and optimization of aspartate aminotransferase 1 inhibitors to target redox balance in pancreatic ductal adenocarcinoma. Bioorg Med Chem Lett 28:2675-2678
Yang, Annan; Herter-Sprie, Grit; Zhang, Haikuo et al. (2018) Autophagy Sustains Pancreatic Cancer Growth through Both Cell-Autonomous and Nonautonomous Mechanisms. Cancer Discov 8:276-287
Santana-Codina, Naiara; Roeth, Anjali A; Zhang, Yi et al. (2018) Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis. Nat Commun 9:4945

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