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: 6667424
• 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: 2002
• 资助国家: 美国
• 起止时间: 2002-09-27 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6667424
• 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：（申请人的描述）卵巢癌化学预防科学发展欠佳，因为难以识别一致的癌前病变或合适的替代终点生物标志物（SEB），缺乏在有疾病风险的患者中测试有前途的化学预防剂的临床策略，并且缺乏公认的动物模型来测试化学预防剂的活性或机制。 该项目旨在解决所有这三个缺陷。 FCCC 研究人员最近发现，因推测卵巢癌风险增加而接受预防性卵巢切除术的女性所摘除的卵巢存在组织学异常（例如，包涵囊肿、表面乳头状瘤病和内陷）。 这些变化可能代表癌前病变，并可被视为新型 SEB。 FCCC 研究人员利用国防部的启动资金启动了一项 II 期化学预防试验，针对患有卵巢癌高风险并希望接受卵巢切除术的女性，使用芬维A胺与安慰剂进行对比；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。 此前已开发出一种独特的卵巢癌动物模型，利用夹取法，将致癌物质，如7,12-二甲基苯并-α蒽（DMBA）直接应用到雌性大鼠的卵巢中，导致卵巢腺癌的发生率高达40%以上。 这种 DMBA 诱导的卵巢癌动物模型可用于测试芬维A胺单独或与其他化学预防剂（如孕激素）组合的化学预防特性，或测试新的潜在感兴趣的化学预防剂。该化学预防项目的目标是：（1）在有卵巢癌风险且选择预防性卵巢切除术的女性中成功开展一系列安慰剂对照、双盲化学预防试验； (2) 与正常卵巢相比，确定从临床试验的两个组中参与者摘除的卵巢中组织病理学标记物的频率以及细胞增殖和凋亡标记物（SEB）的表达，从而前瞻性地验证对癌前表型的初步鉴定； (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，主任 M. Daly）来识别、推荐和监测临床试验的个体，使用遗传易感性测试实验室（核心 3）来确认参与者的资格，并使用组织采购核心来存储和处理卵巢样本。 该项目还利用了 SPORE 生物统计学家的服务。