Sphingosine Kinase as a Target for Cancer Chemoprevention

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DESCRIPTION (provided by applicant): Inflammatory bowel diseases (ulcerative colitis and Crohn's) are chronic inflammatory conditions of the colon. Approximately 4 million people world-wide are affected and are at increased colon cancer risk. Conventional treatment of colitis can reduce periods of active disease and help to maintain remission, but these treatments are often associated with side effects and have marginal results. Sphingolipids are being increasingly recognized as key mediators of cell activation, differentiation and proliferation, and are known to mediate the effects of pro-inflammatory cytokines that are of central importance in colitis-induced colon carcinogenesis. We have shown that specific inhibitors of sphingolipid metabolism, i.e. sphingosine kinase (SK) inhibit colitis in animals. However, we do not know yet whether SK inhibitors stop colon cancer associated with colitis. Here, we propose to test the hypothesis that SK inhibitors prevent colon cancer in mouse models of colitis. These studies should provide important new data that will determine if SK inhibitors provide a new approach that will be useful in preventing the development of colon cancer.