Growth Inhibition Induced by Mifepristone in Ovarian Cancer

描述(申请人提供)：本申请的总体目标是研究将典型的孕激素受体调节剂米非司酮(也称为“RU486”)用于卵巢癌治疗的可行性。卵巢癌是妇女死于妇科疾病的主要原因，部分原因是很难进行早期诊断，也因为缺乏成功的治疗策略。卵巢癌的治疗通常包括细胞减灭术和以铂为基础的化疗，然而这种治疗遇到的主要障碍是化疗耐药性的产生，这导致治疗失败。因此，很明显，迫切需要为晚期疾病患者提供新的治疗方案。我们的初步数据表明，米非司酮不仅对卵巢癌细胞具有细胞抑制作用，而且还能增强标准化疗药物顺铂的细胞毒性。这些结果导致了这样的假设，即米非司酮可以通过两种方式用于治疗：第一，作为一种细胞抑制剂，阻止化疗后存活的细胞重新繁殖；第二，增强化疗诱导的致命性。具体目标1将确定米非司酮对培养的卵巢癌细胞的细胞抑制作用的潜在分子机制，并将在体内使用免疫功能低下的小鼠测试该化合物的疗效。具体目的2，使用遗传背景相似但对顺铂敏感性不同的卵巢癌细胞株，将确定米非司酮是否可以防止顺铂化疗期间癌细胞的再繁殖，以及它增强顺铂介导的致命性的机制。这项研究的结果有可能对人类健康产生重大影响，因为米非司酮与标准的细胞毒性化疗相结合，可以减少细胞毒性药物的有效剂量，从而减少毒副作用，降低化疗耐药性，延长生存期。目前还没有激素疗法被批准用于治疗任何类型的卵巢恶性肿瘤，但我们初步结果的基本原理表明，米非司酮是一种很有前途的激素治疗剂，有望被添加到抗上皮性卵巢癌药物清单中，最终目标是将这种致命的癌症转变为可治疗的慢性疾病。

DESCRIPTION (provided by applicant): The overall goal of this application is to study the feasibility of using the prototypical progesterone receptor modulator mifepristone, also known as "RU486," for ovarian cancer therapeutics. Ovarian cancer is the leading cause of death in women from gynecologic diseases, in part because of the difficulty in performing early diagnosis, and also due to the lack of successful treatment strategies. Treatment for ovarian cancer generally involves cytoreductive surgery followed by platinum-based chemotherapy, yet the major barrier that this treatment encounters is the development of chemoresistance, which leads to therapeutic failure. It is therefore clear that new therapeutic options for patients with advanced disease are desperately needed. Our preliminary data have demonstrated that mifepristone not only is a cytostatic agent for ovarian cancer cells, but also enhances the cytotoxicity of the standard chemotherapeutic agent cisplatin. These results led to the hypothesis that mifepristone can be exploited therapeutically in two manners: first as a cytostatic agent blocking the repopulation of cells that had survived chemotherapy; and second, enhancing chemotherapy-induced lethality. Specific aim 1 will identify the underlying molecular mechanism of the cytostatic effect of mifepristone in cultured ovarian cancer cells, and will test the efficacy of the compound in an in vivo setting using immunocompromised mice. Specific aim 2, using ovarian cancer cell lines of similar genetic backgrounds but carrying different sensitivities to cisplatin, will define whether mifepristone prevents repopulation of cancer cells in between rounds of cisplatin chemotherapy and the mechanism whereby it enhances cisplatin-mediated lethality. Results from this investigation have the potential for a major impact on human health because combination of mifepristone with standard cytotoxic chemotherapy would allow a reduction in the effective dose of cytotoxic drugs leading to reduced toxic side effects, lower chemoresistance and longer survival. At present there is no hormonal therapy approved for the treatment of any type of ovarian malignancy, yet the rationale of our preliminary results suggest that mifepristone is a promising hormonal therapeutic agent to be added to the list of anti-epithelial ovarian cancer drugs with the final goal of converting this lethal cancer into a treatable chronic disease.