Epigenetic Drug Regimens for Homologous Recombination Proficient Ovarian Cancer

多聚ADP核糖聚合酶抑制剂(PARPI)在治疗慢性粒细胞白血病方面显示出非凡的临床疗效。 BRCA突变同源重组(HR)缺陷型卵巢癌。一个严重的临床问题是 包括PARPI在内的化疗药物在BRCA野生型HR熟练患者中的效果要差得多，预后很差 卵巢癌(例如，CCNE1扩增/增益)。将PARPI与其他药物联合使用是一种新兴的策略 克服这个问题。PI已经展示了表观遗传药物，组蛋白脱乙酰酶抑制剂(HDACi)， 溴域末端外抑制物(Beti)和DNA甲基转移酶抑制物(DNMTi)增强PARPI HR熟练型卵巢癌临床前模型的疗效。表观遗传药物主要激活或抑制基因 以细胞类型和上下文相关的方式转录。在CCNE1放大/增益HR精通的背景下 卵巢癌，PI已经证明了化学上不同的表观遗传药物可以诱导一种“类BRCA突变” 背景合成致死表型，以抑制HR基因表达和功能为特征。整体而言 这项建议的目的是确定PARPI疗法的特殊益处是否可以通过 合理的PARPI-表观遗传药物组合作为BRCA野生型HR熟练、差的新适应症 卵巢癌的预后。即使PI的小组和其他人发表了大量的初步结果， 关于临床使用的最佳PARPI表观遗传方案、适当的生物标志物等方面的知识差距仍然存在 应对措施，以及精确的基本行动机制。为了解决这些差距，我们将应用翻译的 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 患者来源的异种移植(PDX)临床前模型，临床患者生物样本与批准的 1/2阶段试验，以及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BRCA野生型HR熟练卵巢癌PARPI疗效的中心假设 通过抑制常见的HR转录靶点和 背景合成杀伤力。这些特定的目标旨在确定新的治疗潜力 PARPI-表观遗传药物方案在卵巢癌临床前模型中的应用 一种新的PARPI-表观遗传药物方案在临床开发中的替代生物标志物及其阐明 对HR敏感的卵巢癌细胞对PARPI-表观遗传药物方案的反应机制 全基因组战略。这种创新的转换方法在推进新的临床前阶段具有很高的潜力 PARPI-表观遗传药物方案用于临床，以及新的生物标记物作为辅助诊断，以及新的 对PARPI和表观遗传药物的机械论见解。因此，拟议的研究将具有广泛的 除了卵巢癌之外的其他影响。因为一个严重的临床问题是缺乏有效的治疗方案 对于BRCA野生型HR熟练者，建立PARPI-表观遗传疗法的益处 卵巢癌的预后有很高的潜在影响。

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.