Targeting RON Receptor Signaling in Pancreatic Cancer

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DESCRIPTION (provided by applicant): The median survival for pancreatic cancer patients remains less than one year. Over the past 3 years, there have been 10 negative Phase III trials investigating systemic treatment of advanced pancreatic cancer with chemo- and biologic agents. The failure of these trials, in large part, reflects our limited understanding of pancreatic cancer biology and demands the rational development of novel agents. We have recently found that the majority of primary and metastatic pancreatic adenocarcinomas over-express the RON receptor tyrosine kinase (RTK). RON is structurally homologous to c-met, an oncogenic protein which is over-expressed and mutated in numerous human cancers. We have shown that activation of RON receptor signaling by its specific ligand, hepatocyte growth factor-like protein (HGFL), induces apoptotic resistance, migration, invasion, association with EGFR, and VEGF production in pancreatic cancer cells. We have identified several key survival pathways that are activated by RON signaling via phosphorylation events and initiation of a unique transcriptional program. Blockade of RON signaling in cell culture can sensitize pancreatic cancer cells to Gemcitabine-induced apoptosis. Finally, we have recently shown that RON-deficient pancreatic cancer xenografts are exquisitely sensitive to Gemcitabine. Using a structure-based approach, we have developed and synthesized a novel small molecule inhibitor to RON (designated MCC5), which maintains the kinase domain in its inactive conformation. Preliminary studies suggest this compound can prevent HGFL-induced phosphorylation of AKT and ERK1/2. Our studies have prompted the following hypotheses; 1) RON receptor signaling regulates pathways critical to pancreatic cancer cell survival and therefore 2) Disruption of the RON signaling axis will sensitize pancreatic cancer to chemo- and biologic therapies. The specific aims of this proposal are; 1) To determine if down-regulation of RON signaling will sensitize pancreatic cancer to Gemcitabine and EGFR directed therapies in an orthotopic model of pancreatic cancer and 2) To complete structure/activity based studies of the novel RON inhibitor, MCC5, in order to define its most biologically active form, and determine whether it can inhibit ligand dependent RON signaling in pancreatic cancer cells. To complete these aims, we will utilize both cell culture assays as well as in vivo fluorescence imaging to monitor tumor-induced nascent blood vessel formation and response to RON targeted mono- and combination therapies. This work will provide powerful preclinical evidence as to the promise of RON targeted therapy for pancreatic cancer. PUBLIC HEALTH RELEVANCE: The life expectancy for patients diagnosed with pancreatic cancer remains less than 1 year and only 4% of patients survive 5 years following diagnosis. Our research group has demonstrated that the RON receptor protein is present on the surface of nearly all pancreatic cancer cells and that RON influences the behavior of these cells, causing them to resist cancer chemotherapies and to invade and spread. In this proposal, we will examine the effects of blocking RON receptor function by two different methods in order to determine if this can reverse pancreatic cancer growth alone and in combination with chemotherapy.