Activating p53 for colorectal cancer prevention

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PROJECT SUMMARY: p53 is a crucial tumor suppressor that stops tumor development in most species and is the most frequently inactivated gene in human cancers. Although about 50% of cancer patients harbor mutant p53, many tumors at early stages of tumor development retain wild type p53. The presence of wild-type p53 in cancer precursor lesions presents an excellent opportunity for chemoprevention by activating p53 to suppress tumor progression. The MDM2 protein is a key negative regulator of p53 and plays a primary role in antagonizing p53 through direct interaction. Small molecule MDM2 inhibitors that block the MDM2–p53 protein–protein interaction would liberate p53 from MDM2, thereby restoring the tumor suppressor function of wild-type p53. We hypothesize that enhancement of wild-type p53 functions by blocking MDM2-p53 interaction in precursor lesions using MDM2 inhibitor is an effective approach for cancer prevention. We propose to test this hypothesis in ApcMin/+ mice, a model for familial adenomatous polyposis. If succeed, our study will pave a new way for cancer chemoprevention.