The c-Met proto-oncogene encodes a transmembrane tyrosine kinase receptor (c-Met) for the ligand hepatocyte growth factor (HGF), a multifunctional protein involved in cancer and metastasis. c-Met gene is located on chromosome 7q, and is encoded by 21 exons. The role of c-Met in pancreatic cancer is currently unknown, and thus we propose to study the c-Met/HGF pathway to ultimately arrive at novel therapy against the devastating pancreatic cancer. Preliminarily, of thirteen pancreatic cancer cell lines studied, there was robust expression of c-Met in 9 of the cell lines. There was signal transduction with HGF in a dose-responsive and kinetic fashion with phosphorylation of c-Met and of downstream targets. The relative expression of c-Met in pancreatic tumor tissues (and adjacent normal where available) as well as the phosphorylated forms of c- Met (pY1003, juxtamembrane (JM) site;pY1230/1234/1235, catalytic site) by constructing tissue arrays has begun. These arrays contain 35-40% African-American (AA) tissues, since this disease can affect AAs more commonly than other races, and hopefully our results may give insight into this difference. It has been shown previously for hereditary papillary renal cell carcinoma there are activating mutations of the c-Met gene in the tyrosine kinase domain, as well there are mutations within the semaphorin (sema) and JM domains for thoracic malignancies, we have started to investigate the potential mutations in pancreatic cancer. Interestingly, we have identified a unique mutation within the sema domain, and this analysis is continuing. Therapeutic inhibition is an important component to pancreatic cancer, and we have begun to elucidate the inhibition of c- Met via several strategies. Using siRNA, small molecule inhibitors, and antibody directed against c-Met, we show in vitro the decrease in cell growth and viability, inhibition of downstream signal transduction via the HGF/c-Met axis, and synergism with mTOR inhibitior. Based on these preliminary findings, we propose these specific aims: 1. Determine the role of c-Met/HGF axis and mutations of c-Met in biological and biochemical functions of pancreatic cancer cells;2. Determine the in vitro and in vivo effects of inhibiting c-Met in pancreatic cancer cells;3. Determine the effects of c-Met/HGF signaling and inhibition on PI3K/AKT/mTOR pathway in pancreatic cancer cells. Our eventual goal is to determine the role of c-Met and arrive at novel therapeutics directed against c-Met in pancreatic cancer. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a devastating illness with an extremely poor prognosis. Novel targeted therapeutics are desparately needed. We have identified that a protein on the cell surface, c-MET receptor tyrosine kinase, can be activated or mutated in pancreatic cancer. Thus, our goal is to study the role of c-MET in human tumor tissues as well as arrive at therapeutics against this target.

R21CA140003

2009-03-01

2012-02-28