Chemoprevention studies in women at high risk for ovarian cancer

卵巢癌高危女性的化学预防研究

• 批准号: 6504971
• 负责人: PAUL Frederick ENGSTROM
• 金额: $ 16.54万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-26 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6504971
• 关键词: biomarker; cancer prevention; cancer risk; chemoprevention; clinical research; female; fenretinide; histology; human subject; human therapy evaluation; laboratory rat; neoplasm /cancer chemotherapy; ovary neoplasms; preneoplastic state; women's health

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.

描述：(申请人描述)卵巢癌化学预防的科学发展缓慢，原因是难以确定一致的癌前病变或合适的替代终点生物标记物(SEB)，缺乏临床策略来测试有患病风险的患者中有前景的化学预防药物，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。这个项目试图解决所有这三个不足之处。Fccc的研究人员最近发现，在接受预防性卵巢切除术的妇女切除的卵巢中，存在组织学异常(如包涵体囊肿、表面乳头状瘤病和凹陷)，这可能会增加卵巢癌的风险。这些变化可能代表癌前病变，并可被认为是新的SEB。Fccc的研究人员利用国防部的启动资金，在卵巢癌高危人群和希望接受卵巢切除术的女性中启动了一项使用非维甲酸和安慰剂的第二阶段化学预防试验；将研究这两组患者的卵巢组织学特征以及细胞增殖和凋亡标记物的相对丰度。以前已经建立了一种独特的卵巢癌动物模型，该模型利用夹闭的方法，允许将致癌物，如7，12-二甲基苯并α菲(DMBA)直接应用于雌性大鼠的卵巢，导致卵巢腺癌的诱发，其相对较高的发病率大于或等于40%。这种DMBA诱导的卵巢癌动物模型可用于测试芬维奈德单独或与其他化学预防药物(如孕激素)联合使用的化学预防性能，或用于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卵巢癌高危女性中成功进行一系列安慰剂对照的双盲化学预防试验；(2)测定组织病理学标志物以及细胞增殖和凋亡标志物(SEBS)在两组临床试验参与者与正常卵巢中的表达频率，从而前瞻性地验证肾癌前病变表型的初步鉴定；(3)利用卵巢癌发生的DMBA模型来测试新的、有希望的卵巢化学预防性药物，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)来确定、转介和监测参加临床试验的个人，使用遗传敏感性测试实验室(核心3)来确认参与者的资格，并使用组织采购核心来储存和处理卵巢标本。该项目还利用了孢子生物统计师的服务。