Epigenetic Drug Regimens for Homologous Recombination Proficient Ovarian Cancer

同源重组卵巢癌的表观遗传药物治疗方案

• 批准号: 10207160
• 负责人: Dineo Khabele
• 金额: $ 32.26万
• 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/10207160
• 关键词: Address; Aftercare; Back; Biological Assay; Biological Markers; Blood specimen; Bromodomain; CCNE1 gene; Cancer Model; Cell Line; ChIP-seq; Chemicals; Clinic; Clinical; Clinical Trials; Complement; DNA Methyltransferase Inhibitor; Data; Drug Combinations; Epigenetic Process; Future; Gene Expression; Genes; Genetic Transcription; Histone Deacetylase Inhibitor; In Vitro; Knowledge; Malignant neoplasm of ovary; Measures; Methods; Molecular; Patients; Pharmaceutical Preparations; Phase I/II Clinical Trial; Phase I/II Trial; Phenotype; Platinum; Poly(ADP-ribose) Polymerases; Positioning Attribute; Pre-Clinical Model; Publishing; Regimen; Repression; Resistance; Surrogate Markers; Testing; Therapeutic; Toxic effect; Translational Research; Validation; Xenograft procedure; antitumor effect; cancer cell; cell type; chemotherapy; clinical development; clinically relevant; companion diagnostics; design; effective therapy; epigenetic drug; epigenetic therapy; gene function; genome-wide; homologous recombination; in vivo; inhibitor/antagonist; innovation; insight; mutant; pre-clinical; preclinical development; prognostic; response; response biomarker; transcriptome sequencing; translational approach; tumor

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.

聚 ADP 核糖聚合酶抑制剂 (PARPi) 在治疗 BRCA 突变同源重组 (HR) 缺陷卵巢癌。一个关键的临床问题是 化疗药物，包括 PARPi，对于 BRCA 野生型 HR 熟练、预后不良的患者效果要差得多 卵巢癌（例如 CCNE1 扩增/增益）。将 PARPi 与其他药物结合是一种新兴策略 克服这个问题。 PI 展示了表观遗传药物、组蛋白脱乙酰酶抑制剂 (HDACi)、 溴结构域额外末端抑制剂 (BETi) 和 DNA 甲基转移酶抑制剂 (DNMTi) 增强 PARPi HR 熟练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进行转录。在 CCNE1 扩增/获得 HR 熟练的背景下 卵巢癌，PI 已证明化学多样化的表观遗传药物可诱导“BRCA 突变样” 背景合成致死表型，其特征是 HR 基因表达和功能受到抑制。整体 该提案的目的是确定 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 的新适应症 熟练，差 卵巢癌的预后。即使 PI 小组和其他人已经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、适当的生物标志物方面仍然存在知识差距 反应和精确的潜在作用机制。为了解决这些差距，我们将应用翻译 研究方法充分利用我们的集体专业知识，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，与批准的相关的临床患者生物样本 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 中心假设是表观遗传药物增强 PARPi 对 BRCA 野生型 HR 熟练卵巢癌的疗效 通过抑制常见的 HR 转录靶标诱导 BRCA 突变体样表型， 情境综合杀伤力。具体目标旨在确定新药物的治疗潜力 卵巢癌临床前模型中的 PARPi-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 HR 熟练卵巢癌细胞对 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推进新的临床前研究的巨大潜力 临床上的 PARPi-表观遗传药物方案，以及作为伴随诊断的新生物标志物，以及新的 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 影响超出卵巢癌范围。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，确定 PARPi 表观遗传疗法对这种典型贫困肿瘤的益处 卵巢癌的预后具有重大影响的潜力。