Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death and is driven mostly by mutated Kras gene. Despite advances in our understanding of the pathogenesis of PDAC, the disease remains highly refractory to treatment. In this proposal, we will employ genome scale approaches to identify potential signaling nodes and druggable targets that will be used for therapeutics development for PDAC patients. Based on our preliminary data and technical capabilities, we proposed the following specific aims.
Aim #1) To identify co-extinction targets for combination therapeutics against KRAS* PDAC. The goal of this aim is to identify candidate targets that when co-extinguished can lead to suppression or death of KRAS* PDAC tumor cells. Both genetic and pharmacological approaches will be used, taking advantage of strengths of both mouse and human systems, as well as leveraging the emerging comprehensive genomic data on human PDAC. Co-extinction target candidates identified in more than one system will be prioritized for in-depth biological, functional as well as clinical pathological validation.
Aim #2) To identify resistance mechanism to KRas inhibition. The goal of this aim is to proactively anticipate and elucidate possible molecular basis for resistance in setting of Kras* inhibition. We will apply a novel in vivo context-specific genetic screen approach to identify and functionally validate genes that promote survival of PDAC cells following KRas inactivation, initially focusing on the kinases followed by genetic elements of interests defined by comprehensive genomics by ICGC PDAC project. Furthermore, we will engineer GEM models with the most promising resistant hits to validate resistance mechanism in vivo and to test new therapeutic strategy against such resistance mechanisms.

Public Health Relevance

Pancreatic cancer remains incurable despite advances in our understanding of its pathogenesis. In this proposal, we will employ various state of the art technologies to identify therapeutic intervention points that will lead to cell death or proliferation arrest of KRas driven pancreatic cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA117969-09
Application #
8603764
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
9
Fiscal Year
2014
Total Cost
$406,836
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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
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:

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