Chemoprevention studies in women at high risk for ovarian cancer

产品说明：卵巢癌化学预防的科学发展很差，因为难以鉴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处于疾病风险中的患者中有希望的化学预防剂，以及缺乏可接受的动物模型来测试化学预防剂活性或机制。 本项目旨在解决所有这三个缺陷。FCCC研究人员最近发现了组织学异常（例如，内含物囊肿、表面乳头状瘤病和内陷），这些病变是由于推测卵巢癌风险增加而接受预防性卵巢切除术的妇女切除的卵巢。 这些变化可能代表瘤前病变，并可被视为新型SEB。 FCCC研究人员利用国防部的启动资金，在卵巢癌高危女性中开展了一项II期化学预防试验，使用芬维A胺与安慰剂，并希望接受卵巢切除术;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，该模型通过利用剪切方法，允许将致癌物如7，12-二甲基苯并α蒽（DMBA）直接应用于雌性大鼠的卵巢中，这导致卵巢腺癌的诱导，其相对高的发病率大于或等于40%。 该DMBA诱导的卵巢癌动物模型可用于测试单独的芬维A胺或与其他化学预防剂如孕激素组合的化学预防性质，或测试感兴趣的新的潜在化学预防剂。本化学预防计划的目标是：（1）成功地在选择预防性卵巢切除术的卵巢癌高危妇女中进行一系列安慰剂对照、双盲化学预防试验;（2）检测组织病理学标志物的频率以及细胞增殖和凋亡标志物（SEBs）的表达与正常卵巢相比，从临床试验的两个组的参与者中取出的卵巢中，因此前瞻性地验证了肿瘤前表型的初步鉴定，以及;（3）利用DMBA卵巢癌模型来测试新的、有希望的卵巢化学预防剂，并更好地理解这些药物的作用机制。项目4使用OCCN（核心1，M。Daly，主任），以确定，转介和监测个人的临床试验，遗传易感性测试实验室（核心3），以确认参与者的资格和组织采购核心储存和处理卵巢标本。 该项目还利用了SPORE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.