Chemoprevention studies in women at high risk for ovarian cancer

（申请人描述）由于难以确定一致的癌前病变或合适的替代终点生物标志物（seb），缺乏临床策略来测试有希望的化学预防药物在有疾病风险的患者中，以及缺乏公认的动物模型来测试化学预防药物的活性或机制，卵巢癌化学预防科学发展不佳。本项目旨在解决所有这三个缺陷。FCCC研究人员最近发现，在接受预防性卵巢切除术的女性卵巢中，有组织学异常（如包涵性囊肿、表面乳头状瘤病和内翻），这些卵巢可能会增加卵巢癌的风险。这些变化可能代表肿瘤前病变，可考虑为新的seb。FCCC研究人员利用国防部的启动资金启动了一项II期化学预防试验，在患卵巢癌高风险并希望接受卵巢切除术的妇女中使用芬瑞啶与安慰剂对照；我们将研究两组患者卵巢的组织学特征以及细胞增殖和凋亡标志物的相对丰度。以前已经开发了一种独特的卵巢癌动物模型，该模型利用剪切方法，允许将致癌物，如7,12 -二甲基苯- α蒽（DMBA）直接应用于雌性大鼠的卵巢，从而诱导卵巢腺癌，其发病率相对较高，大于或等于40%。该DMBA诱导的卵巢癌动物模型，可用于测试芬瑞啶单独或与其他化学预防药物（如黄体酮）联合的化学预防性能，或测试新的潜在化学预防药物。该化学预防项目的目标是：(1)在选择预防性卵巢切除术的有卵巢癌风险的妇女中成功进行一系列安慰剂对照、双盲化学预防试验；(2)与正常卵巢相比，确定两组临床试验参与者卵巢中组织病理学标志物的频率和细胞增殖与凋亡标志物（SEBs）的表达，从而前瞻性地验证肿瘤前表型的初步鉴定；(3)利用卵巢癌发生的DMBA模型来检测新的、有前途的卵巢化学预防药物，并更好地了解这些药物的作用机制。项目4使用OCCN（核心1，M. Daly，主任）为临床试验识别、转诊和监测个体，使用遗传易感性测试实验室（核心3）确认参与者资格，使用组织采购中心储存和处理卵巢标本。该项目还利用了孢子生物统计学家的服务。

DESCRIPTION: (Applicant's Description) 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.