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

摘要 子宫内膜癌是由激素驱动的，是美国主要的妇科癌症。 在这些肿瘤中，高达80%的肿瘤存在PTEN功能缺失。目前的治疗方法 晚期和复发的癌症疗效有限，预后尤其差。 少数族裔，如黑人妇女，死于子宫癌的几率要高出60% 与白人患者相比。PARP抑制剂是一种口服药物，可以选择性地杀死 DNA同源修复(HR)途径存在缺陷的细胞。使用活体小鼠模型 我们已经证明，口服PARP抑制剂奥拉帕利可以有效地靶向子宫内膜 在雌激素缺乏的荷尔蒙环境中，PTEN缺失是唯一的基因改变的肿瘤。我们 假设(A)PTEN功能障碍足以使子宫内膜肿瘤对PARP敏感 尽管存在累积的遗传变化，但仍存在抑制和(B)高雌激素状态 子宫内膜癌患者中常见的诱导表达和功能增加 导致对PARP抑制剂产生抗性的HR途径蛋白。为了检验这些假设，我们将 利用(A)我们实验室研制的子宫内膜癌小鼠模型 概述了人类疾病和(B)人类子宫内膜癌 加州大学洛杉矶分校的生物信息库。PARP和芳香酶抑制剂都是口服的药物 与化疗和化疗相比，更便宜，耐受性更好，更容易管理 辐射。我们建议的疗法如果有效，可以通过使 低收入和少数人更容易获得子宫内膜癌的门诊治疗 病人。此外，如果发现抑制PARP对侵袭性子宫内膜有效 癌症，它们的使用可能会增加黑人女性的生存结果 不成比例地受晚期癌症影响。

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.