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. ? ? ?
|Zhang, Lei; Hapon, Maria B; Goyeneche, Alicia A et al. (2016) Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or lysosome inhibitors. Mol Oncol 10:1099-117|
|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|
|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|
|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|
|Tieszen, Chelsea R; Goyeneche, Alicia A; Brandhagen, BreeAnn N et al. (2011) Antiprogestin mifepristone inhibits the growth of cancer cells of reproductive and non-reproductive origin regardless of progesterone receptor expression. BMC Cancer 11:207|
|Freeburg, Elizabeth M; Goyeneche, Alicia A; Seidel, Erin E et al. (2009) Resistance to cisplatin does not affect sensitivity of human ovarian cancer cell lines to mifepristone cytotoxicity. Cancer Cell Int 9:4|
|Villavicencio, A; Goyeneche, A; Telleria, C et al. (2009) Involvement of Akt, Ras and cell cycle regulators in the potential development of endometrial hyperplasia in women with polycystic ovarian syndrome. Gynecol Oncol 115:102-7|
|Freeburg, Elizabeth M; Goyeneche, Alicia A; Telleria, Carlos M (2009) Mifepristone abrogates repopulation of ovarian cancer cells in between courses of cisplatin treatment. Int J Oncol 34:743-55|