Evaluation of Src Inhibition in Pancreas Cancer

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DESCRIPTION (provided by applicant): Pancreatic adenocarcinoma is the fourth leading cause of cancer deaths annually, with over 37,000 new cases and over 32,000 deaths estimated for 2007. Despite recent improved understanding of pancreas cancer biology, the 5-year survival remains at 4% despite multimodality therapy. The continued poor survival despite the new understanding of pancreatic cancer biology and the incorporation of novel therapies demonstrates an acute need for improvement in therapy. To this end, a patient-derived pancreatic adenocarcinoma explant xenograft model, the "PancBank", has been created to help develop novel therapies for pancreatic cancer. One emerging target is the non-receptor kinase, c-SRC. This protein regulates multiple cascades that impact cellular adhesion, migration and invasion, factors that when dysregulated enable tumor cells to disrupt their microenvironment, travel to distant sites and invade host tissues independent of normal regulatory signals. The result of this phenotype is metastasis, the critical mechanism by which cancer cells cause organ dysfunction and ultimately death. As with most targeted therapies, it is critically important to search for correlative biomarkers of drug efficacy in order to properly select patients. We have used novel oral Src inhibitors in the PancBank to compare sensitive and resistant human pancreas cancer explants, and have found interesting leads using gene profiling analysis and Western blotting. The next step is to explore these preliminary findings in the clinic. The goal is to complete a phase II clinical and biological study of AZD0530, an oral Src inhibitor, in gemcitabine-resistant metastatic pancreas cancer patients. This is a CTEP-approved and funded protocol run through the Phase II Consortium, and the principal investigator of this proposal wrote the protocol and serves as its national chair. Using correlative studies including pre- and post-tumor biopsies, PET scans, and PK studies, this clinical trial represents a highly unique opportunity to qualify and extend the results of the human xenograft experiments in pancreas cancer. The central hypothesis, which is supported by our preliminary data, is that a subset of patients who can be identified in predictive manner with our correlative studies will derive benefit from AZD0530. These studies will identify biomarkers that can be tested in a larger phase III study in the future, and also point the way towards drug combinations with Src inhibitors. PUBLIC HEALTH RELEVANCE: The purpose of this grant is to explore what properties of pancreas cancer are associated with vulnerability, or resistance, to Src inhibitors. We will use several methods to analyze patient tumor samples from the clinical protocol NCI#7602, "A Phase II Trial of AZD0530 in Previously Treated Metastatic Pancreas Cancer." AZD0530 is a novel oral inhibitor of Src, which was of the first cancer-causing genes discovered several decades ago, and it is hoped the results will help guide us to better use of such drugs in the clinic.