Epigenetic Drug Regimens for Homologous Recombination Proficient Ovarian Cancer

聚ADP核糖聚合酶抑制剂（PARPi）在治疗糖尿病中显示出非凡的临床益处。 BRCA突变体同源重组（HR）缺陷型卵巢癌。一个关键的临床问题是 化疗药物，包括PARPi，在BRCA野生型HR患者中的疗效要差得多， 卵巢癌（例如CCNE 1扩增/获得）。将PARPi与其他药物结合是一种新兴的策略， 克服这个问题。PI已经显示了表观遗传药物，组蛋白脱乙酰酶抑制剂（HDACi）， 布罗莫结构域末端外抑制剂（BETi）和DNA甲基转移酶抑制剂（DNMTi）增强PARPi 在HR正常卵巢癌临床前模型中的疗效。表观遗传药物主要激活或抑制基因 以细胞类型和上下文依赖的方式转录。在CCNE 1放大/获得HR熟练的背景下 卵巢癌，PI已经证明化学多样的表观遗传药物诱导“BRCA突变样” 背景合成致死表型，其特征在于HR基因表达和功能受到抑制。整体 本提案的目的是确定PARPi疗法的非凡益处是否可以通过以下方式扩展 合理的PARPi-表观遗传药物组合用于BRCA野生型HR熟练、不良的新适应症 卵巢癌的预后即使有广泛的出版和初步的结果，从PI的小组和其他人， 关于临床使用的最佳PARPi表观遗传方案、适当的生物标志物 以及精确的潜在作用机制。为了解决这些差距，我们将应用一个 充分利用我们的集体专业知识的研究方法，包括：独特的原代细胞系和 患者源性异种移植物（PDX）临床前模型，与已批准的 1/2期试验和最先进的全基因组策略。因此，我们完全有能力测试 表观遗传药物增强PARPi在BRCA野生型HR功能正常卵巢癌中的疗效的中心假设 通过抑制常见HR转录靶点诱导BRCA突变体样表型， 关联合成致命性特定目的旨在确定新的治疗潜力 PARPi-卵巢癌临床前模型中的表观遗传药物方案，以研究HR缺陷状态作为 临床开发中新PARPi-表观遗传药物方案的替代生物标志物，并阐明 在HR熟练的卵巢癌细胞中使用PARPi-表观遗传药物方案的反应机制 全基因组策略。这种创新的转化方法具有很高的潜力，可用于推进新的临床前 PARPi-表观遗传药物方案的临床，沿着新的生物标志物作为伴随诊断， PARPi和表观遗传药物的机制见解。因此，拟议的研究将具有广泛的 卵巢癌以外的影响因为一个关键的临床问题是缺乏有效的治疗方案 对于BRCA野生型HR熟练肿瘤，建立PARPi表观遗传治疗对这种典型的不良反应的益处， 预后卵巢癌具有潜在的高影响。

Poly ADP ribose polymerase inhibitors (PARPi) have shown extraordinary clinical benefits in the treatment of BRCA mutant homologous recombination (HR) deficient ovarian cancer. A critical clinical problem is chemotherapy drugs, including PARPi, are far less effective in BRCA wild-type HR proficient, poor prognostic ovarian cancer (e.g. CCNE1 amplification/gain). Combining PARPi with other drugs is an emerging strategy to overcome this problem. The PI has shown epigenetic drugs, histone deacetylase inhibitors (HDACi), bromodomain extra-terminal inhibitors (BETi), and DNA methyltransferase inhibitors (DNMTi), enhance PARPi efficacy in preclinical models of HR proficient ovarian cancer. Epigenetic drugs primarily activate or repress gene transcription in a cell type- and context-dependent manner. In the context of CCNE1 amplified/gain HR proficient ovarian cancer, the PI has demonstrated chemically diverse epigenetic drugs induce a “BRCA mutant-like” contextual synthetic lethal phenotype, characterized by repressed HR gene expression and function. The overall objective of this proposal is to determine if the extraordinary benefits of PARPi therapy can be extended through rational PARPi-epigenetic drug combinations for a new indication in BRCA wild-type HR proficient, poor prognostic ovarian cancer. Even with extensive published and preliminary results from the PI's group and others, gaps in knowledge remain regarding optimal PARPi-epigenetic regimens for clinical use, appropriate biomarkers of response, and precise underlying mechanisms of action. To address these gaps, we will apply a translational research approach that takes full advantage of our collective expertise including: unique primary cell lines and patient-derived xenograft (PDX) preclinical models, clinical patient biosamples associated with an approved phase 1/2 trial, and state-of-the-art genome-wide strategies. As a result, we are perfectly positioned to test the central hypothesis 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. The Specific Aims are designed to determine the therapeutic potential of new PARPi-epigenetic drug regimens in preclinical models of ovarian cancer, to investigate HR deficient status as a surrogate biomarker of a new PARPi-epigenetic drug regimen in clinical development, and to elucidate mechanisms of response to PARPi-epigenetic drug regimens in HR proficient ovarian cancer cells using genome-wide strategies. This innovative translational approach has high potential for advancing new preclinical PARPi-epigenetic drug regimens to the clinic, along with new biomarkers as companion diagnostics, and new mechanistic insights for both PARPi and epigenetic drugs. As a result, the proposed studies will have broad implications beyond ovarian cancer. Because a critical clinical problem is the lack of effective treatment options for BRCA wild-type HR proficient tumors, establishing benefits of PARPi-epigenetic therapy for this typically poor prognostic ovarian cancer has the potential for high impact.