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

基本信息

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
项目类别：
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

项目摘要

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由激素驱动的，是美国主要的妇科癌症。高达 80% 的此类肿瘤中发现 PTEN 功能丧失。目前的治疗方法晚期和复发性癌症的疗效有限，并且结果特别差黑人女性等少数族裔死于子宫癌的几率高出 60% 与白人患者相比。 PARP 抑制剂是一种口服药物，可选择性杀死 DNA 同源修复 (HR) 途径有缺陷的细胞。使用体内小鼠模型我们已经证明奥拉帕尼（Olaparib）是一种口服 PARP 抑制剂，可以有效靶向子宫内膜在雌激素缺乏的荷尔蒙环境中，PTEN 缺失是唯一的基因变化的肿瘤。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和（b）高雌激素状态，但仍受到抑制常见于子宫内膜癌患者，诱导表达和功能增加 HR 通路蛋白导致对 PARP 抑制剂产生耐药性。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，该模型密切概括了人类疾病和 (b) 德鲁和库中储存的人类子宫内膜癌加州大学洛杉矶分校生物样本库。 PARP 和芳香酶抑制剂都是口服药物与化疗相比，价格便宜、耐受性更好且更容易施用辐射。我们提出的疗法如果有效，可以通过以下方式减少治疗差异：低收入和少数族裔更容易获得子宫内膜癌的门诊治疗患者。此外，如果发现 PARP 抑制可有效对抗侵袭性子宫内膜癌症，它们的使用可能会增加患有癌症的黑人妇女的生存结果受晚期癌症的影响尤为严重。