Pancreatic cancer is an exceptionally aggressive cancer. It is the fourth leading cause of cancer death in the United States and is increasing in incidence. One of the major factors contributing to the high fatality of pancreatic cancer is the poor responses of most pancreatic cancer patients to radio- and chemo-therapy. Our long-term goal is to understand the molecular mechanisms underlying the exceptional radio- and chemo-resistance in pancreatic cancer. We have recently succeeded in creating pancreatic cancer isogenic cell lines that differ in radiosensitivity from the parental cells. The radioresistant cel lines were generated by exposing pancreatic cancer cells to fractionated ionizing radiation programmed in a way that mimics a typical course of radiotherapy. We hypothesize that the acquired radioresistance in the pancreatic cancer cells are conferred by the aberrant expression of one or more proteins that are involved in cell proliferation and/or survival. Our preliminary results show that several pathways in the radioresistant pancreatic cancer cells have been markedly altered. We propose to use advanced subcellular fractionations, novel quantitative proteomic profiling, and bioinformatics analysis to systematically identify the proteins that are mostly likely to be responsible for the acquired radioresistance in the pancreatic cancer cells (Specific Aim 1), and use molecular and cell biology methods to functionally characterize a well-defined set of the identified proteins with regards to their roles in radio- and chemoradio-resistance in pancreatic cancer (Specific Aim 2). The results from the proposed work will contribute to understanding the molecular mechanisms underlying the exceptional radio- and chemoradio-resistance in pancreatic cancer, and will contribute to designing new strategies to improve the cure rate of pancreatic cancer.

Public Health Relevance

Pancreatic cancer is an exceptionally aggressive cancer. One of the major factors contributing to the high fatality of pancreatic cancer is the poor responses of most pancreatic cancer patients to radio- and chemo-therapy. The objective of this project is to use a genetically defined isogenic cell model and a novel quantitative proteomic method to identify the proteins that may confer radioresistance in pancreatic cancer cells, and then use molecular/cell biology methods to validate the functions of the identified proteins. The results from the proposed work are expected to contribute to designing new strategies to improve the cure rate of pancreatic cancer.

Agency
National Institute of Health (NIH)
Type
Small Research Grants (R03)
Project #
5R03CA169692-02
Application #
8692678
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Bernhard, Eric J
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Arkansas at Fayetteville
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Fayetteville
State
AR
Country
United States
Zip Code
72701