Research Description

Evaluation of the in vivo effects of novel agents that target FAK and IGF-1R binding in pancreatic cancer

FAK and IGF-1R integrate signals from many important molecules and mediate cancer cell survival functions. Pancreatic cancer is an aggressive malignancy with redundant survival pathways and Dr. Hochwald has previously shown that FAK physically interacts with IGF-1R to provide essential survival signals for pancreatic cancer cells. Utilizing non cell based assays with GST and HIS tagged purified proteins, his laboratory has demonstrated direct physical interaction between a FAK amino terminus fragment (NT2) and the kinase domain of IGF-1R. Subsequently, computer modeling has demonstrated that the binding regions on both FAK and IGF-1R, defined by structural analysis, were appropriate targets for small drug-like molecule binding. To screen for small molecules that could disrupt binding between FAK and IGF-1R, his laboratory combined molecular docking in silico with functional testing in pancreatic cancer cell lines. Previously, this method was successfully applied to protein kinases and other targets. Using the NCI/Developmental Therapeutics Program (DTP) chemical library data base of 140,000 compounds, the small molecules with the highest probability of binding to FAK NT2 and disrupting the interaction with IGF-1R were obtained. His laboratory has identified and characterized lead small molecule compounds that target the interaction site of FAK and IGF-1R, disrupt the binding between FAK and IGF-1R, inhibit pancreatic cancer cell viability, decrease IGF-1R and Akt phosphorylation, and induce apoptosis.

For the summer research program, I will evaluate the effects of these inhibitors on the growth of human pancreatic cancer in vivo. Specifically, I will learn and perform immuno-histochemistry on pancreatic cancer tumors obtained from nude mice that have been treated with these small molecule inhibitors. These tumors will be stained for expression of FAK, IGF-1R, Akt, ERK, Ki67 and caspase-3 to determine if the inhibitors decrease FAK and IGF-1R expression, as well as alter downstream signaling, decrease cell proliferation, or induce apoptosis. In addition, I will be performing cell viability screening assays to evaluate whether more novel inhibitors can be identified that target FAK and IGF-1R interaction in pancreatic cancer as well as other cancers including esophageal cancer.