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

项目摘要/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。相当大的子集 高级别浆液性卵巢癌(HGSC)精通HR并对PARPI耐药；因此导致 预后不良的卵巢癌(CCNE1扩增/增益)。HR熟练型卵巢的临床前模型 癌症研究表明，将PARPI与表观遗传药物相结合，产生了“类似BRCA突变的”上下文-- 合成致死表型；其特征是HR基因的表达和功能受到抑制。《少年派》 已经证明了成功地将组蛋白脱乙酰酶抑制剂(HDACi)、溴域Extra-Go. 末端抑制物(Beti)和DNA甲基转移酶抑制物(DNMTi)与PARPI在临床前模型中的联合应用 人力资源熟练程度。然而，在最佳联合疗法方面仍然存在差距。在我们的父母赠款中，我们 表观遗传药物增强BRCA野生型HR熟练卵巢癌PARPI疗效的假说 通过抑制常见的HR转录靶点和 背景合成杀伤力。与传统的2D原代培养不同，有机物培养提供了一种独特的体外培养 模型更好地概括了组织形态和细胞异质性。我们假设那个病人- 衍生有机化合物是肿瘤微环境的较好代表，可用于筛查一线和 治疗卵巢癌的新型药物组合。我们将追求两个具体目标：1)评估患者- 卵巢衍生有机类化合物对奥拉帕利和铂的敏感性，然后筛选PARPI和 表观遗传药物联合治疗和2)确定生物标记物以评估肿瘤对 奥拉帕利和内抑素联合治疗，使用从可用的患者活检组织和 PI的临床试验。此外，来自基金R01的数据，这一补充将导致新的组合 治疗策略和确定替代生物标记物以评估治疗效率。

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.