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Antiprogestin therapy for ovarian cancer

卵巢癌的抗孕激素治疗

基本信息

批准号：
8231087
负责人：
Carlos Marcelo Telleria
金额：
$ 42.56万
依托单位：
UNIVERSITY OF SOUTH DAKOTA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-19 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8231087
关键词：
Animal Model Biomedical Research Cancer Patient Cell Cycle Cell Cycle Kinetics Cell Death Cells Cessation of life Chemosensitization Chronic Chronic Disease Cisplatin Clinic Clinical Clinical Trials Design Contraceptive Agents Cyclin-Dependent Kinase Inhibitor Cytostatics DNA Repair Data Development Diagnosis Disease Dose Drug toxicity Estrogen Antagonists Exposure to FDA approved Feasibility Studies Female Female Genital Diseases G2 Phase Goals Greater sac of peritoneum Growth Healthcare In Vitro Laboratories Lead Life Maintenance Therapy Malignant Neoplasms Malignant neoplasm of ovary Mammalian Oviducts Mediating Mifepristone Modality Modeling Molecular Neoplasm Metastasis Operative Surgical Procedures Ovary Pathway interactions Patients Pharmaceutical Preparations Platinum Platinum Compounds Progesterone Receptors Recurrence Relapse Reproductive Medicine Research Proposals Resistance Schedule Site Staging Survival Rate Testing Therapeutic Therapeutic Intervention Time Toxic effect Translations Treatment Efficacy Tumor Burden Tumor Debulking Uterus Woman Work base cancer cell cancer therapy cell growth chemotherapy clinically relevant cohort design human CDK2 protein improved in vivo malignant breast neoplasm mouse model novel therapeutic intervention pre-clinical preclinical study prevent reproductive senescence success

项目摘要

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.

描述（由申请人提供）：本申请的总体目标是研究“重新定位”最初设计用于卵巢癌治疗的避孕目的的抗孕激素化合物的可行性。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，进入了附近的输卵管、子宫和腹膜腔内的各个其他部位。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，这种疗法的功效受到铂衍生物毒性升高、治疗间隔之间细胞重新增殖以及逃避药物毒性机制发展的阻碍。因此，发现克服铂类治疗局限性的治疗干预措施具有重要的临床意义。我们的实验室证明，使用原型抗孕激素米非司酮进行单一治疗可在体外以及卵巢癌临床前体内动物模型中抑制卵巢癌细胞的生长。我们最近证明抗孕激素药物 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，在致死剂量的顺铂疗程后，抗孕激素米非司酮的存在可以通过增强顺铂的致死性来防止顺铂治疗中幸存的残余卵巢癌细胞的再增殖或再生长。这些结果导致了这样的假设：抗孕激素可用于治疗卵巢癌，从而增强铂类化疗的疗效。为了检验这一假设，具体目标 1 将使用卵巢癌原位小鼠模型来研究抗孕激素米非司酮是否能提高顺铂的体内治疗效果，该模型类似于疾病的两个关键阶段，包括卵巢内的原发性生长和腹腔内的继发性传播（转移）。具体目标 2 将阐明抗孕激素在卵巢癌细胞中增强铂类致死性的分子机制，特别强调 DNA 损伤/修复途径，并将确定抗孕激素增强铂类致死性是否需要孕酮受体。具体目标 3 将评估抗孕激素介导的卵巢癌细胞在逃脱铂毒性后重新增殖的生长抑制机制，并确定长期暴露于抗孕激素的细胞在铂逃脱后的长期命运。这些临床前研究将提供原理证明，证明抗孕激素（其中米非司酮已被 FDA 批准用于生殖医学）可以重新用于另一种使用方式，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。 PUBLIC HEALTH RELEVANCE: Ovarian cancer is the most deadly disease of the female reproductive tract and has historically been called the "silent killer."该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在治疗上增强铂类化疗对卵巢癌的疗效。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，并且在过去三十年中没有出现重大的治疗突破。该提案中描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孕激素，最终目的是提高患者的生活质量和数量，并将这种致命的癌症转化为可控制的慢性疾病。