) The science of ovarian cancer chemoprevention is poorly developed because of difficulties identifying a consistent premalignant lesions or suitable surrogate endpoint bio-markers (SEBs), the lack of a clinical strategy to test promising chemoprevention agents in patients at risk for the disease and the absence of an accepted animal model to test chemoprevention agent activity or mechanisms. This project seeks to address all three of these deficiencies. FCCC investigators have recently identified histologic abnormalities (e.g., inclusion cysts, surface papillomatosis, and invaginations) in ovaries removed from women undergoing prophylactic oophorectomy for presumed increased risk of ovarian cancer. These changes may represent preneoplastic lesions and could be considered novel SEBs. FCCC investigators have utilized start-up funds from the Department of Defense to initiate a phase II chemoprevention trial utilizing Fenretinide versus a placebo in women who are at high risk of developing ovarian cancer and desire to undergo oophorectomy; the histologic characteristics of the ovaries and the relative abundance of markers of cell proliferation and apoptosis from the two groups of patients will be studied. A unique animal model of ovarian cancer has been previously developed which, by utilizing the clipping method, allows the direct application of carcinogens, such as 7, 12-dimethylbenz alpha anthracene (DMBA), into the ovaries of female rats which results in the induction of ovarian adenocarcinomas with a relative high incidence greater than or equal to 40 percent. This DMBA induced ovarian carcinoma animal model, can be used to test the chemopreventive properties of Fenretinide alone or with combination with other chemopreventive agents such as progestins, or to test new potential chemoprevention agents of interest. The objectives of this chemoprevention project are: (1) to successfully conduct a series of placebo controlled, double-blind chemoprevention trials in women at risk for ovarian cancer who elect prophylactic oophorectomy; (2) to determine the frequency of histopathology markers and expression of markers of cell proliferation and apoptosis (SEBs) in the ovaries removed from participants in the two arms of the clinical trial compared to normal ovaries, thus prospectively validating the initial identification of the preneoplastic phenotype, and; (3) to utilize the DMBA model of ovarian carcinogenesis to test new, promising ovarian chemopreventive agents and to better understand the mechanism of action of these agents. Project 4 uses the OCCN (Core 1, M. Daly, Director) to identify, refer and monitor individuals for the clinical trial, the Genetic Susceptibility Testing Laboratory (Core 3) for confirming participant eligibility and the Tissue Procurement Core for storage and processing ovarian specimens. This project also utilizes the services of the SPORE biostatistician.
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