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 #
5P01CA117969-08
Application #
8507157
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
8
Fiscal Year
2013
Total Cost
$342,658
Indirect Cost
$13,900
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Mullarky, Edouard; Lairson, Luke L; Cantley, Lewis C et al. (2016) A novel small-molecule inhibitor of 3-phosphoglycerate dehydrogenase. Mol Cell Oncol 3:e1164280
Saung, May Tun; Sharei, Armon; Adalsteinsson, Viktor A et al. (2016) A Size-Selective Intracellular Delivery Platform. Small :
Kugel, Sita; Sebastián, Carlos; Fitamant, Julien et al. (2016) SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b. Cell 165:1401-15
Sousa, Cristovão M; Biancur, Douglas E; Wang, Xiaoxu et al. (2016) Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536:479-83
Mullarky, Edouard; Lucki, Natasha C; Beheshti Zavareh, Reza et al. (2016) Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers. Proc Natl Acad Sci U S A 113:1778-83
Huang, Yinshi; Nahar, Sabikun; Nakagawa, Akifumi et al. (2016) Regulation of GLI Underlies a Role for BET Bromodomains in Pancreatic Cancer Growth and the Tumor Microenvironment. Clin Cancer Res 22:4259-70
Ying, Haoqiang; Dey, Prasenjit; Yao, Wantong et al. (2016) Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 30:355-85
Dayton, Talya L; Gocheva, Vasilena; Miller, Kathryn M et al. (2016) Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma. Genes Dev 30:1020-33
Tummala, Krishna S; Kottakis, Filippos; Bardeesy, Nabeel (2016) NRF2: Translating the Redox Code. Trends Mol Med 22:829-831
Chakrabarti, Gaurab; Moore, Zachary R; Luo, Xiuquan et al. (2015) Targeting glutamine metabolism sensitizes pancreatic cancer to PARP-driven metabolic catastrophe induced by ß-lapachone. Cancer Metab 3:12

Showing the most recent 10 out of 103 publications