The goal for this renewal application is to gain in-(depth knowledge of PI3K and RAS-MAPK signaling with cooperating pathways governing pancreatic ductal adenocarcinoma (PDAC) to guide clinical trials with prominent drug development candidates and to identify new therapeutic points of attack in these pathways. The program project consists of a multiple-disciplinary team of basic and clinical investigators with a strong track record of working together and with complementary strengths In tumor biology, mouse genetics, cancer metabolism, PI3K signaling and functional genomics. The Program consists of 3 highly Interactive projects (Project 1: DePinho. Hahn and Chin. DFCi: Project 2: Cantley. BIDMC and Bardeesy. MGH: Project 3: Jacks and Van der Heiden. MIT) with the integrating goals of determining the roles of KRAS* synthetic lethal genes in PDAC development and maintenance, the effect of co-extinction of PI3K/MEK pathways In PDAC and associated drug resistance mechanisms, the Impact of MEK/PI3K inhibition on PDAC metabolism, and the effect of inhibiting glutamine metabolism on PDAC. Project 1 will employ whole genome RNAi and bioinformatics analyses to identify and validate druggable coextinction targets that synergize with MEKi or Pi3Ki in suppressing KRAS* PDACs. In addition, context specific gain of function in vivo genetic screens Will be performed to identify additional druggable targets underlying acquired resistance or playing cooperative roles with Pi3K/MEK signaling. Project 2 will address the central hypothesis that KRAS*-driven PDAC utilizes the PI3K and MAPK pathways in a redundant way to drive tumor growth and that a critical role for these pathways involves the maintenance of tumor metabolism. Project 2 will determine the impact of MEKi/PiSKi on PDAC cell signaling, metabolism, and therapeutic response. These efforts will be coupled with an investigation of metabolic biomarkers for MEK/Pi3K signaling and identification of mechanisms of therapeutic resistance which would be critical in guiding future therapeutic trials In this area. Project 3 will investigate the importance of a series of potential therapeutic targets in tumor maintenance by developing both conditional RNAi systems for use in cell culture and transplant models as well as sophisticated genetically-engineered mouse models designed to allow conditional deletion of genes in autochthonous tumors. These Projects Will be enabled by highly innovative cores for Molecular Imaging (Weissleder. MGH). Experimental Pathology (Loda/Chu. DFCl). Biobank (Thayer. MGH). and Mouse Engineering (DePinho/Homer. DFCi): and assisted by an administrative core to provide scientific and fiscal oversight (DePinho, DFCl).

Public Health Relevance

Pancreatic cancer represents the fourth leading cause of cancer death and remains incurable. This program project aims to identify therapeutic intervention points through various state-of-the-art technologies and animal modeling. The goal remains to gain sufficient understanding of RDAC genetics and biology to info the implementation of effective therapeutic combinations for locally advanced and metastatic diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA117969-09
Application #
8603762
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (O1))
Program Officer
Jhappan, Chamelli
Project Start
2006-04-15
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
9
Fiscal Year
2014
Total Cost
$1,908,631
Indirect Cost
$227,453
Name
University of Texas MD Anderson Cancer Center
Department
Biology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Nejati, Reza; Goldstein, Jennifer B; Halperin, Daniel M et al. (2017) Prognostic Significance of Tumor-Infiltrating Lymphocytes in Patients With Pancreatic Ductal Adenocarcinoma Treated With Neoadjuvant Chemotherapy. Pancreas 46:1180-1187
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Pergolini, Ilaria; Morales-Oyarvide, Vicente; Mino-Kenudson, Mari et al. (2017) Tumor engraftment in patient-derived xenografts of pancreatic ductal adenocarcinoma is associated with adverse clinicopathological features and poor survival. PLoS One 12:e0182855
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Shukla, Surendra K; Purohit, Vinee; Mehla, Kamiya et al. (2017) MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer. Cancer Cell 32:71-87.e7
Dey, Prasenjit; Baddour, Joelle; Muller, Florian et al. (2017) Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer. Nature 542:119-123

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