FAK and IGF-1R interaction in pancreatic cancer survival

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DESCRIPTION (provided by applicant): This proposed five-year training program seeks to expand the applicant's knowledge in advanced molecular biology with the goals of: 1) pursuing a hypothesis-driven, mechanistic understanding, in both in vitro and in vivo models, of the role of focal adhesion kinase (FAK) and insulin-like growth factor receptor (IGF-1R) in promoting pancreatic cancer cell survival; and 2) to provide the applicant with the skills needed to develop a translational research program for the application of targeted molecular therapeutics. Training components have been integrated and thoughtfully constructed to help the applicant reach his long-term career goal of developing a successful independent research program that understands cancer cell biology and develops novel molecular approaches to cancer treatment. Pancreatic cancer remains a major unsolved health problem in the United States with the death rate of patients with this disease similar to the incidence. Novel therapies are needed in this disease to improve patient survival. FAK and IGF-1R are tyrosine kinases whose overexpression occurs in pancreatic cancer. Both have been reported to be important survival signals for tumor cells to resist apoptosis as well as promoters of invasion and proliferation. The hypothesis that will be tested is whether activated IGF-1R, IRS-1 (critical mediator of IGF-1R signaling) and FAK physically interact and synergize as important survival signals in human pancreatic adenocarcinoma cells. Studies outlined will seek to elucidate the mechanism of interaction between FAK and IGF-1R in these cells and to determine if inhibition of both FAK and IGF-1R simultaneously will more efficiently inhibit cell invasion, adhesion, proliferation and potentiate apoptosis. Binding domains between FAK, IRS-1 and IGF-1R will be evaluated with the use of GST and HIS fusion proteins. Apoptotic pathways that are activated following FAK and IGF-1R inhibition will be determined. FAK and IGF-1R activity will be inhibited with the use of selective small molecule tyrosine kinase inhibitors and with the expression of dominant negative forms to both. The ability of small molecule tyrosine kinase inhibitors of FAK and IGF-1R to inhibit growth of human pancreatic tumors, will be studied in a nude mouse animal model. This application represents the first attempts at targeting both of these kinases in human pancreatic cancer.