Antiprogestin therapy for ovarian cancer

描述（由申请人提供）：本申请的总体目标是研究将最初设计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。当疾病被诊断出来时，在大多数情况下，异常生长已经超出了卵巢的范围，并进入附近的输卵管，子宫和腹膜腔内的各种其他部位。因此，大多数诊断为卵巢癌的患者需要手术，然后进行铂类化疗。然而，铂衍生物的毒性升高、治疗间隔之间的细胞再增殖以及逃避药物毒性的机制的发展阻碍了这种疗法的功效。因此，发现治疗性干预措施以克服铂类药物治疗的局限性具有重要的临床意义。我们的实验室证明，在体外以及在卵巢癌的临床前体内动物模型中，使用原型抗孕激素米非司酮的单一疗法抑制卵巢癌细胞的生长。我们最近证明抗卵巢癌蛋白剂ORG-31710和CDB-2914也抑制卵巢癌生长。最后，我们的初步数据表明，存在的抗孕激素米非司酮后，顺铂的致死剂量的课程，防止复发或再生长的残留卵巢癌细胞生存顺铂治疗增强顺铂的致死率。这些结果导致了一种假设，即抗孕激素可用于卵巢癌的治疗，提高铂类化疗的疗效。为了检验这一假设，具体目标1将调查是否antirexistin米非司酮提高顺铂的治疗效果，在体内使用原位小鼠模型的卵巢癌类似于两个关键阶段的疾病，包括原发性生长在卵巢和继发性传播在腹膜腔（转移）。具体目标2将阐明抗孕激素增强铂在卵巢癌细胞中的致死性的分子机制，特别强调DNA损伤/修复途径，并将确定孕激素受体是否是抗孕激素增强铂诱导的致死性所必需的。具体目标3将评估抗孕激素介导的卵巢癌细胞生长抑制的机制，这些细胞在逃避铂的毒性后重新增殖，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抗孕激素-其中米非司酮被FDA批准用于生殖医学-可以重新用于另一种使用模式，作为卵巢癌患者化疗药物的一部分，最终目标是改善他们的生活质量和数量，并显着延长这种毁灭性疾病的5年生存率。 公共卫生相关性：卵巢癌是女性生殖道最致命的疾病，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卵巢癌药物是否可以在治疗上提高卵巢癌铂类化疗的疗效。该项目的完成预计将对关键的医疗保健问题产生重大影响，因为卵巢癌仍然是所有妇科疾病中最致命的疾病，并且在过去三十年中没有出现重大的治疗突破。本提案中所述的临床前研究的完成将导致临床试验的合理设计，包括用于治疗卵巢癌的抗肿瘤素，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化为可管理的慢性疾病。

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.