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.
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.
|Zhang, Lei; Hapon, Maria B; Goyeneche, Alicia A et al. (2016) Mifepristone increases mRNA translation rate, triggers theÂ unfolded protein response, increases autophagic flux, andÂ kills ovarian cancer cells in combination with proteasomeÂ or lysosome inhibitors. Mol Oncol 10:1099-117|
|Goyeneche, Alicia A; Telleria, Carlos M (2015) Antiprogestins in gynecological diseases. Reproduction 149:R15-33|
|Gamarra-Luques, Carlos D; Hapon, Maria B; Goyeneche, Alicia A et al. (2014) Resistance to cisplatin and paclitaxel does not affect the sensitivity of human ovarian cancer cells to antiprogestin-induced cytotoxicity. J Ovarian Res 7:45|
|Brandhagen, BreeAnn N; Tieszen, Chelsea R; Ulmer, Tara M et al. (2013) Cytostasis and morphological changes induced by mifepristone in human metastatic cancer cells involve cytoskeletal filamentous actin reorganization and impairment of cell adhesion dynamics. BMC Cancer 13:35|
|Wempe, Stacy L; Gamarra-Luques, Carlos D; Telleria, Carlos M (2013) Synergistic lethality of mifepristone and LY294002 in ovarian cancer cells. Cancer Growth Metastasis 6:1-13|
|Telleria, Carlos M (2013) Repopulation of ovarian cancer cells after chemotherapy. Cancer Growth Metastasis 6:15-21|
|Telleria, Carlos M (2012) Drug Repurposing for Cancer Therapy. J Cancer Sci Ther 4:ix-xi|
|Goyeneche, Alicia A; Seidel, Erin E; Telleria, Carlos M (2012) Growth inhibition induced by antiprogestins RU-38486, ORG-31710, and CDB-2914 in ovarian cancer cells involves inhibition of cyclin dependent kinase 2. Invest New Drugs 30:967-80|
|Gamarra-Luques, Carlos D; Goyeneche, Alicia A; Hapon, Maria B et al. (2012) Mifepristone prevents repopulation of ovarian cancer cells escaping cisplatin-paclitaxel therapy. BMC Cancer 12:200|