ACTIVATION OF C SRC IN PANCREATIC CANCER BY FGFR 1B

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DESCRIPTION (Applicant's Description): Pancreatic cancer is one of the most lethal tumors seen in medicine today. Following diagnosis of this condition, less than 4% of patients are expected to survive beyond 5 years. Understanding the resilience of pancreatic tumor cells will require elucidation of molecular mechanisms regulating cell growth anc transformation during neoplasia. Ongoing studies in this and other laboratories have identified the enhanced appearance of FGF ligands, an alteratively spliced isoform of the FGF receptor (FGFR-1beta) iNOS and total nitrotyrosine in target polypeptides. Preliminary studies demonstrate that FGF-activated signaling through FGFR-1beta promotes growth and the survival of pancreatic epithelial cells in response to chemotherapy, radiation treatment and peroxynitrite (ONOO-) apoptosis, an observation accompanied by the appearance of activated c-Src containing phosphorylated and nitrated tyrosine residues. These observations imply pivotal interdependent roles for ONOO and FGF signaling during tumor growth and metastatic behavior. Experimental aims are designed within the framework of the hypothesis that the clinically aggressive chemo- and radio-resistant features of pancreatic adenocarcinoma are the consequences of interdependent signaling of reactive nitrogen species and ligand-activated FGFR-1beta to c- Src. An underlying theme includes quantitating the production and targeted molecular responses to ONOO that modulate FGF/FGFR-1beta signal transduction pathways. The availability of specific molecular reagents, established techniques, defined human and rat cell populations, relevant rodent models, and clinical specimens permits fundamental mechanistic studies to elucidate molecular events responsible for the cause and effect interrelationship between oxidant stress and FGF biology. Detailed characteristics of these interrelationships should provide diagnostic criteria for monitoring this devastating disease and identify rational strategies to combat pancreatic cancer.