Epigenetic Drug Regimens for Homologous Recombination Proficient Ovarian Cancer - Diversity Supplement

用于同源重组熟练卵巢癌的表观遗传药物治疗方案 - Diversity Supplement

• 批准号: 10599719
• 负责人: Dineo Khabele
• 金额: $ 6.95万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599719
• 关键词: Advanced Development; Ascites; Biological Assay; Biological Markers; Biopsy; Bromodomain; CCNE1 gene; Cancer Etiology; Cancer cell line; Carboplatin; Cessation of life; Clinical; Clinical Trials; Combination Drug Therapy; Combined Modality Therapy; DNA Methyltransferase Inhibitor; Data; Drug Combinations; Epigenetic Process; Funding; Gene Expression; Genetic; Genetic Transcription; Goals; Heterogeneity; Histone Deacetylase Inhibitor; Human; In Vitro; Investigation; Laboratories; Malignant Female Reproductive System Neoplasm; Malignant neoplasm of ovary; Methods; Molecular; Morphology; Mus; Neoplasm Metastasis; Organoids; Outcome; Ovarian; Parents; Patients; Phenotype; Platinum; Poly(ADP-ribose) Polymerases; Pre-Clinical Model; Primary Neoplasm; Protocols documentation; Publishing; Regimen; Repression; Resistance; Sampling; Serous; Surrogate Markers; System; Testing; Therapeutic; Tissue Banks; Tissues; United States; Woman; Work; antitumor effect; base; burden of illness; chemotherapy; epigenetic drug; epigenetic therapy; gene function; homologous recombination; improved; improved outcome; in vitro Model; in vivo; inhibitor; inhibitor therapy; interest; mutant; novel; novel drug combination; novel marker; ovarian neoplasm; parent grant; preclinical study; prognostic; response; screening; single-cell RNA sequencing; success; tumor; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Ovarian cancer is the deadliest gynecologic cancer and is the fifth leading cause of cancer death among women in the United States. Poly (ADP-ribose) polymerase inhibitors (PARPi) have long been used in the treatment BRCA mutant homologous-recombination (HR) deficient ovarian cancers. A substantial subset of high-grade serous ovarian cancers (HGSC) are HR proficient and are resistant to PARPi; thus resulting in poor prognostic ovarian cancers (CCNE1 amplification/gain). Preclinical models of HR proficient ovarian cancer have shown that combining PARPi with epigenetic drugs, resulted in “BRCA mutant-like” contextual- synthetic lethal phenotype; which was characterized by repressed HR gene expression and function. The PI has demonstrated the success of combining histone deacetylase inhibitors (HDACi), bromodomain extra- terminal inhibitors (BETi), and DNA methyltransferase inhibitors (DNMTi) with PARPi in preclinical models of HR proficiency. However, gaps still remain in the optimal combination therapy. In our parent grant, we hypothesized that epigenetic drugs enhance PARPi efficacy in BRCA wild-type HR proficient ovarian cancer by inducing a BRCA mutant-like phenotype through repression of common HR transcriptional targets and contextual synthetic lethality. Unlike traditional 2D primary cultures, organoid cultures provide a unique in vitro model which better recapitulates tissue morphology and cellular heterogeneity. We hypothesize that patient- derived organoids are better representatives of the tumor microenvironment for screening of first-line and novel drug combinations to treat ovarian cancer. We will pursue two Specific Aims: 1) Evaluate patient- derived ovarian organoids for olaparib and platinum sensitivity, followed by the screening of PARPi and epigenetic drugs combination therapy and 2) Identify biomarkers to assess the status of tumor response to olaparib and entinostat combination therapy, using organoids developed from available patient biopsies and the PI’s clinical trial. In addition data from the funded R01, this supplement will lead to novel combination therapeutic strategies and the identification of surrogate biomarkers to assess treatment efficiency.

项目总结/摘要 卵巢癌是最致命的妇科癌症，是癌症死亡的第五大原因， 美国的女性。聚（ADP-核糖）聚合酶抑制剂（PARPi）长期以来一直被用于 治疗BRCA突变同源重组（HR）缺陷型卵巢癌。一个重要的子集， 高级别浆液性卵巢癌（HGSC）是HR熟练的，对PARPi有抗性;因此导致 预后不良的卵巢癌（CCNE 1扩增/获得）。HR熟练卵巢的临床前模型 癌症研究表明，PARPi与表观遗传药物相结合，导致了“BRCA突变体样”的背景- 合成致死表型;其特征在于抑制HR基因表达和功能。的PI 已经证明了将组蛋白去乙酰化酶抑制剂（HDACi）、溴结构域外- 末端抑制剂（BETi）和DNA甲基转移酶抑制剂（DNMTi）与PARPi在临床前模型中的作用 精通人力资源。然而，在最佳联合治疗方面仍然存在差距。在我们的父母补助金，我们 假设表观遗传药物增强PARPi在BRCA野生型HR熟练卵巢癌中的疗效 通过抑制常见HR转录靶点诱导BRCA突变体样表型， 关联合成致命性与传统的2D原代培养物不同，类器官培养物提供了独特的体外培养方法。 更好地概括组织形态学和细胞异质性的模型。我们假设病人- 衍生的类器官是肿瘤微环境的更好代表， 治疗卵巢癌的新药物组合。我们将追求两个具体目标：1）评估患者- 用于奥拉帕尼和铂敏感性的衍生的卵巢类器官，然后筛选PARPi和 表观遗传药物联合治疗和2）鉴定生物标志物以评估肿瘤对表观遗传药物联合治疗的反应状态。 奥拉帕尼和恩替司他联合治疗，使用从可用的患者活检中开发的类器官， 私家侦探的临床试验除了来自受资助的R 01的数据，该补充剂将导致新的组合 治疗策略和鉴定替代生物标志物以评估治疗效率。