PARP inhibition with hormonal modulation as a therapy for PTEN driven endometrial tumors

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Abstract Endometrial carcinomas are hormonally driven and the leading gynecologic cancer in the U.S. Loss of PTEN function is identified in up to 80% of these tumors. Current therapies for advanced and recurrent cancers have limited efficacy, and outcomes are particularly poor in minorities such as black women who have a 60% greater chance of dying from uterine cancer compared to white patients. PARP inhibitors are orally administered drugs that selectively kill cells with defects in the DNA homologous repair (HR) pathway. Using an in vivo mouse model we have demonstrated that Olaparib, an oral PARP inhibitor, can effectively target endometrial tumors with PTEN-loss as a sole genetic change in an estrogen deprived hormonal milieu. We hypothesize that (a) PTEN dysfunction is sufficient to sensitize endometrial tumors to PARP inhibition despite the presence of cumulative genetic changes and (b) a hyper-estrogenic state commonly seen in endometrial cancer patients induces increased expression and function of HR pathway proteins causing resistance to PARP inhibitors. To test these hypotheses we will utilize (a) an endometrial cancer mouse model developed by our laboratory that closely recapitulates human disease and (b) human endometrial cancers banked at the Drew and UCLA bio-repositories. Both PARP and aromatase inhibitors are orally administered agents that are inexpensive, better tolerated and more easily administered compared to chemotherapy and radiation. Our proposed therapy if effective could decrease treatment disparities by making outpatient therapies for endometrial cancer more readily available to low-income and minority patients. Additionally, if PARP inhibition is found to be effective against aggressive endometrial cancers, their use could potentially increase survival outcomes for black women who are disproportionately affected by advanced cancers.