Mutations that result in constitutively active K-RAS are found in over 95% of PDACs and are believed to be an initiating event for this type of cancer. Despite the high frequency of K-RAS mutations in PDAC and other cancers, efforts to date to develop therapies directed against the oncoprotein have failed. This failure has led to a focus on the effector pathways controlled by K-RAS as possible therapeutic targets (see Project 2). Project 3 is based on an alternative strategy for inhibiting the growth of K-RAS-mutant cells, which is rooted in recent success of our group and others in identifying so-called """"""""K-RAS synthetic lethal genes"""""""". Several such genes have been identified through RNAi screens and other strategies as being required selectively In K-RAS mutant cancer cells. However, none of these genes have been adequately examined in vivo as potential tumor maintenance genes and none have been validated in the context of P DAC.
In Aim 1 of Project 3, we will use RNAi and biochemical methods to investigate the effects of inhibiting four candidate synthetic lethal genes/pathways?STK33, TBK1, NF-{K}B, and the M2 isoform of the pyruvate kinase gene (PK-M2)?in PDAC-derived cell lines of mouse and human origin.
In Aim 2, we will create a novel mouse model of PDAC that will allow for the assessment of these and other candidate tumor maintenance genes in the context of established PDAC. Using a combination of conditional alleles controlled by two site-specific recombinases (Cre and Flp), this model will allow for conditional activation of K-RAS (with or without accompanying mutation In p53) to promote PDAC development, followed by conditional inactivation of the gene of interest. This system will be deployed first to test the consequences of inhibiting Stk33, Tbk1 or PK-M2 In established, autochthonous tumors. Additional potential tumor maintenance genes identified in this project and other projects in this PO1 will be tested In the future.
In Aim 3, we will use the systems developed In Aim 1 to conduct a broader screen of candidate synthetic lethal genes that might be useful in the development of therapies for PDAC. These data will tie used to prioritize genes that will be further tested in the in vivo system developed in Aim 2.

Public Health Relevance

Pancreatic ductal adenocarcinoma (PDAC) is a major unsolved health problem. Worldwide, over 213,000 patients will develop pancreatic cancer in 2009, and nearly all will die of their disease. Our work will result in the identification of novel targets in adenocarcinoma maintenance, in settings that closely resemble the human disease. Our research will ultimately allow testing the effects of putative small-molecule inhibitors of these novel targets in our mouse models, both on the tumor and on the normal tissue.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
United States
Zip Code
Biancur, Douglas E; Paulo, Joao A; Ma?achowska, Beata et al. (2017) Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism. Nat Commun 8:15965
Ravez, Séverine; Corbet, Cyril; Spillier, Quentin et al. (2017) ?-Ketothioamide Derivatives: A Promising Tool to Interrogate Phosphoglycerate Dehydrogenase (PHGDH). J Med Chem 60:1591-1597
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
Cancer Genome Atlas Research Network. Electronic address:; Cancer Genome Atlas Research Network (2017) Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell 32:185-203.e13
Lu, Xin; Horner, James W; Paul, Erin et al. (2017) Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature 543:728-732
Lyssiotis, Costas A; Kimmelman, Alec C (2017) Metabolic Interactions in the Tumor Microenvironment. Trends Cell Biol 27:863-875
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
Sherman, Mara H; Yu, Ruth T; Tseng, Tiffany W et al. (2017) Stromal cues regulate the pancreatic cancer epigenome and metabolome. Proc Natl Acad Sci U S A 114:1129-1134
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

Showing the most recent 10 out of 121 publications