Targeting KRAS for Pancreatic Cancer Treatment
Abstract
Background: The Congressionally directed Topic Area of our proposal is pancreatic cancer, the cancer with the highest frequency of RAS mutations (95%). Our studies also indirectly but significantly address two other Congressionally directed Topic Areas, colorectal cancer and melanoma, cancers with the second (50%) and fifth (30%) highest frequency of RAS mutations. The Military Relevance Focus Area is "Gaps in cancer prevention, diagnosis, early detection, or treatment that may affect the general population but have a particularly profound impact on military health." The idea and reasoning behind our proposed studies is based on the near 100% frequency of KRAS oncogene mutations in pancreatic cancer. It is widely accepted that if aberrant KRAS function can be blocked, a significant clinical response will be seen for pancreatic cancer. With an uncertain likelihood of success with currently pursued directions, we reason that new approaches and targets are needed if we are to succeed in developing the long-elusive anti-K-Ras drug. Objective/Hypothesis: The objective of our studies is to identify novel targets for the development of anti-Ras therapeutic strategies for pancreatic cancer. We hypothesize that, utilizing a cell model not previously evaluated, a comprehensive profiling of mutant KRAS-dependent molecular and biochemical activities will achieve this objective. The overall goal will be the development of an anti-KRAS chemotherapeutic approach for pancreatic cancer treatment. Specific Aims: (1) To define the molecular portrait of KRAS-dependency. (2) To identify the cancer signaling pathways that drive KRAS dependency. Study Design: We will employ a human cancer cell-based strategy where short-term shRNA suppression of KRAS expression in a panel of KRAS-mutant pancreatic cancer patient xenograft (PDX)-derived cell lines will be done. In Aim 1, control and KRAS-suppressed cell populations will then be evaluated for changes in RNA expression, DNA methylation, protein expression, and protein phosphorylation and signal activation. Together, these studies will provide the most comprehensive molecular profiling of KRAS-dependency to be done. In Aim 2, a bar-coded lentivirus expression library encoding activated signaling components of networks altered in pancreatic cancer will be used to identify signaling mechanisms that allow pancreatic cancer cells to lose their addiction to mutant KRAS. Innovation: To date, four widely utilized cell models have been studied to identify KRAS-dependent molecular processes that drive pancreatic cancer growth. While each has strengths, each is also compromised by distinct limitations. We propose a fifth approach, one that overcomes the limitations of the four currently pursued directions. We propose short-term shRNA silencing of mutant KRAS expression and oncogenesis in a panel of pancreatic cancer patient xenograft (PDX)-derived cell lines. This cell model has significant advantages over the more widely utilized established pancreatic cancer cell lines studied to date. Military Relevance: Pancreatic cancer is currently the fourth major cause of cancer deaths for US active duty Service members, their families, and other military beneficiaries. It is projected to be the second leading cause by around 2020. Currently, the 5-year survival rate of this deadly cancer is 6%. Therefore, in addition to loss of lives, this cancer significantly and deleteriously impacts the quality of life and productivity of US military personnel.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510611
Entities
People
- Channing Der
Organizations
- United States Army
- University of North Carolina at Chapel Hill