Growth Inhibition Induced by Mifepristone in Ovarian Cancer

描述（由申请人提供）：本申请的总体目标是研究使用原型孕酮受体调节剂米非司酮（也称为“RU 486”）用于卵巢癌治疗的可行性。卵巢癌是妇科疾病导致妇女死亡的主要原因，部分原因是难以进行早期诊断，也是由于缺乏成功的治疗策略。卵巢癌的治疗通常包括细胞减灭术，然后进行铂类化疗，但这种治疗遇到的主要障碍是化疗耐药性的产生，从而导致治疗失败。因此，很明显，迫切需要为晚期疾病患者提供新的治疗选择。我们的初步数据表明，米非司酮不仅是卵巢癌细胞的细胞生长抑制剂，但也增强了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进行治疗：第一，作为细胞生长抑制剂，阻断化疗后存活的细胞的再增殖;第二，增强化疗诱导的致死性。具体目标1将确定米非司酮在培养的卵巢癌细胞中的细胞抑制作用的潜在分子机制，并将使用免疫受损小鼠在体内环境中测试化合物的功效。具体目标2，使用卵巢癌细胞系相似的遗传背景，但携带不同的敏感性顺铂，将确定米非司酮是否防止再增殖的癌细胞之间的顺铂化疗轮和机制，从而提高顺铂介导的致死率。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细胞毒性化疗的组合将允许减少细胞毒性药物的有效剂量，从而减少毒副作用，降低耐药性和延长生存期。目前，没有激素治疗批准用于治疗任何类型的卵巢恶性肿瘤，但我们的初步结果的理由表明，米非司酮是一种有前途的激素治疗剂添加到列表中的抗上皮性卵巢癌药物的最终目标是将这种致命的癌症转化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.