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

通过激素调节抑制 PARP 作为治疗 PTEN 驱动的子宫内膜肿瘤的方法

• 批准号: 9041148
• 负责人: Sanaz Memarzadeh
• 金额: $ 3.75万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9041148
• 关键词: Address; Adipocytes; Advanced Malignant Neoplasm; Affect; Androgens; Area; Aromatase; Aromatase Inhibitors; Back; Cancer Center; Cancer Patient; Clinical Trials; Collaborations; DNA; DNA Sequence Alteration; Defect; Endometrial Carcinoma; Endometrial Neoplasms; Estrogen Metabolism; Estrogens; Excision; Functional disorder; Hormonal; Hormones; Human; Laboratories; Low income; Malignant Female Reproductive System Neoplasm; Maps; Mediating; Minority; Mus; Mutation; Obesity; Oral; Outcome; Outpatients; Ovary; PARP inhibition; PTEN gene; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pilot Projects; Postdoctoral Fellow; Production; Proteins; Radiation; Recurrent Malignant Neoplasm; Refractory; Reporting; Research; Research Project Grants; Residual state; Resistance; Site; Students; Testing; Therapeutic; Uterine Cancer; Weight; Woman; Work; abstracting; base; cancer health disparity; cell killing; chemotherapy; combinatorial; differential expression; effective therapy; homologous recombination; human disease; in vivo; inhibitor/antagonist; mouse model; recombinational repair; repaired; repository; response; tumor

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.

抽象的 子宫内膜癌是荷尔蒙驱动的，并且是美国领先的妇科癌症 在这些肿瘤中，多达80％的PTEN功能丧失。当前的疗法 晚期和经常性癌症的疗效有限，结果尤为差 少数民族（例如黑人妇女）有60％的可能死于子宫癌 与白人患者相比。 PARP抑制剂是口服的药物，有选择地杀死 DNA同源修复（HR）途径缺陷的细胞。使用体内鼠标模型 我们已经证明了口服PARP抑制剂Olaparib可以有效地靶向子宫内膜 雌激素剥夺的激素环境中，具有PTEN损害的肿瘤是唯一的遗传变化。我们 假设（a）PTEN功能障碍足以使子宫内膜肿瘤敏感 尽管存在累积遗传变化和（b）过度源性状态，但抑制作用 在子宫内膜癌症患者中通常会发现 HR途径蛋白会引起对PARP抑制剂的抗性。为了检验这些假设，我们将 利用（a）我们实验室开发的子宫内膜癌小鼠模型 概括人类疾病和（b）在Drew和 加州大学洛杉矶分校的生物重新构件。 PARP和芳香酶抑制剂都是口服的药物 与化学疗法和 辐射。我们提出的治疗如果有效可以通过使治疗差异减少 低收入和少数族裔更容易获得子宫内膜癌的门诊疗法 患者。另外，如果发现PARP抑制作用有效，则针对侵略性子宫内膜 癌症，他们的使用可能会增加黑人妇女的生存成果 受高级癌症的影响不成比例。