Antiprogestin therapy for ovarian cancer

描述(申请人提供)：本申请的总体目标是研究将原本用于避孕目的的抗孕激素化合物“重新定位”用于卵巢癌治疗的可行性。卵巢癌是女性生殖道最致命的疾病。确诊时，大多数情况下，异常生长已经超出卵巢的范围，进入附近的输卵管、子宫和腹膜腔内的各种其他部位。因此，大多数被诊断为卵巢癌的患者需要手术，然后进行以铂为基础的化疗。然而，铂衍生物的毒性升高、治疗间隔期间细胞的重新繁殖以及逃避药物毒性的机制的发展阻碍了这种治疗的有效性。因此，发现治疗干预措施以克服以铂为基础的治疗的局限性具有重要的临床意义。我们的实验室证明，单独使用典型的抗孕激素米非司酮在体外和临床前的体内卵巢癌动物模型中都能抑制卵巢癌细胞的生长。我们最近证实，抗孕激素药物ORG-31710和CDB-2914也能抑制卵巢癌的生长。最后，我们的初步数据表明，在致命剂量的顺铂疗程后，抗孕激素米非司酮的存在通过增强顺铂的致死性来阻止顺铂治疗后残留的卵巢癌细胞的再繁殖或再生长。这些结果导致假设抗孕激素可以用于卵巢癌的治疗，提高以铂为基础的化疗的疗效。为了验证这一假设，特定目标1将使用卵巢癌的两个关键阶段-卵巢癌的两个关键阶段-卵巢内的原发生长和腹膜腔内的继发转移(转移)，在体内调查抗孕激素米非司酮是否改善了顺铂的治疗效果。具体目标2将阐明抗孕激素增强铂对卵巢癌细胞的致死性的分子机制，特别是DNA损伤/修复途径，并将确定是否需要孕酮受体来增强抗孕激素对铂诱导的致死性。具体目标3将评估抗孕激素对逃脱铂毒性后重新生长的卵巢癌细胞的生长抑制机制，并确定铂逃逸后长期暴露于抗孕激素的细胞的长期命运。这些临床前研究将提供原则证据，即抗孕激素--其中米非司酮被FDA批准用于生殖医学--可以被重新用于另一种方式，作为卵巢癌患者化疗工具的一部分，最终目标是改善他们的生活质量和数量，并显著延长这种毁灭性疾病的5年存活率。 公共卫生意义：卵巢癌是女性生殖道中最致命的疾病，历史上被称为“沉默的杀手”。这项研究计划将研究最初设计用于避孕目的的抗孕激素药物是否可以用于治疗，以提高以铂为基础的化疗对卵巢癌的疗效。由于卵巢癌仍然是所有妇科疾病中最致命的疾病，而且在过去30年中没有出现重大的治疗突破，预计该项目的完成将对一个关键的卫生保健问题产生重大影响。完成这项建议中描述的临床前研究将导致合理设计临床试验，包括用于治疗卵巢癌的抗孕激素，最终目的是改善患者的生活质量和数量，并将这种致命的癌症转变为一种可控制的慢性病。

DESCRIPTION (provided by applicant): The overall goal of this application is to study the feasibility of "repositioning" antiprogestin compounds originally designed for contraceptive purposes for ovarian cancer therapeutics. Ovarian cancer is the most deadly disease of the reproductive tract in women. When the disease is diagnosed, in most cases abnormal growths have already progressed beyond the confines of the ovaries and into the nearby fallopian tubes, uterus, and various other sites within the peritoneal cavity. As a result, the majority of patients diagnosed with ovarian cancer require surgery followed by platinum-based chemotherapy. Yet the efficacy of this therapy is hindered by the elevated toxicity of platinum derivatives, the repopulation of cells between treatment intervals, and the development of mechanisms to evade drug toxicity. Thus, the discovery of therapeutic interventions to overcome the limitations of platinum-based therapy is of critical clinical relevance. Our laboratory demonstrated that single therapy with the prototypical antiprogestin mifepristone inhibits growth of ovarian cancer cells in vitro as well as in a preclinical in vivo animal model of ovarian cancer. We have recently proved that the antiprogestin agents ORG-31710 and CDB-2914 also inhibit ovarian cancer growth. Finally, our preliminary data indicate that presence of the antiprogestin mifepristone after courses of lethal doses of cisplatin prevents repopulation or regrowth of remnant ovarian cancer cells surviving cisplatin treatment by potentiating cisplatin lethality. These results led to the hypothesis that antiprogestins can be exploited therapeutically in ovarian cancer enhancing the efficacy of platinum-based chemotherapy. To test the hypothesis, Specific Aim 1 will investigate whether antiprogestin mifepristone improves the therapeutic efficacy of cisplatin in vivo using orthotopic mouse models of ovarian cancer resembling two key stages of the disease including primary growth within the ovary and secondary dissemination in the peritoneal cavity (metastasis). Specific Aim 2 will elucidate the molecular mechanism whereby antiprogestins potentiate platinum lethality in ovarian cancer cells with particular emphasis on the DNA damage/repair pathways, and will determine whether progesterone receptors are required for the potentiation by antiprogestins of platinum-induced lethality. Specific Aim 3 will assess the mechanisms involved in antiprogestin-mediated growth inhibition of ovarian cancer cells that had repopulated after escaping the toxicity of platinum, and define the long-term fate of cells chronically exposed to antiprogestins after platinum escape. These pre-clinical studies will provide proof-of-principle that antiprogestins -of which mifepristone is FDA approved for reproductive medicine- can be repurposed for another modality-of-use as part of the chemotherapeutic armamentarium for ovarian cancer patients with the final goal of improving their quality and quantity of life, and significantly extending the 5-yr survival rate of this devastating disease. PUBLIC HEALTH RELEVANCE: Ovarian cancer is the most deadly disease of the female reproductive tract and has historically been called the "silent killer." This research proposal will study whether antiprogestin drugs originally designed for contraceptive purposes can be exploited therapeutically enhancing the efficacy of platinum-based chemotherapy for ovarian cancer. Accomplishment of this project is anticipated to have high impact on a critical health care problem as ovarian cancer still is the most deadly of all gynecologic diseases and no significant therapeutic breakthrough has occurred during the past three decades. The completion of the pre-clinical studies described in this proposal will lead to the rational design of clinical trials including an antiprogestin for the treatment of ovarian cancer with the final purpose of improving the quality and quantity of life of patients, and converting this lethal cancer into a manageable chronic disease.