Synthetic lethality based combination approaches to ARID1A mutation in ovarian cancer

基于合成致死率的卵巢癌 ARID1A 突变组合方法

• 批准号: 10192683
• 负责人: Rugang Zhang
• 金额: $ 50.98万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-18 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192683
• 关键词: 3-Dimensional; ARID1A gene; Acetylation; Apoptosis; Apoptotic; Catalytic Domain; Cells; Chromatin Remodeling Factor; Chromatin Structure; Clinical; Data; Dependence; Diagnosis; Disease; Down-Regulation; EZH2 gene; Epigenetic Process; Epithelial ovarian cancer; Gene Expression; Genes; Genetic; Goals; HDAC6 gene; Human; Intervention; Knowledge; Lysine; Malignant Neoplasms; Malignant neoplasm of ovary; Methods; Mission; Modality; Molecular; Mutate; Mutation; Outcome; Ovarian Clear Cell Tumor; Ovarian Endometrioid Adenocarcinoma; Platinum; Post-Translational Protein Processing; Pre-Clinical Model; Primary Neoplasm; Prognosis; Public Health; Refractory; Research; Resistance; Role; SMARCA4 gene; SWI/SNF Family Complex; Series; TP53 gene; Testing; Therapeutic; Tumor Suppressor Proteins; United States National Institutes of Health; Up-Regulation; Xenograft Model; base; cancer cell; cancer subtypes; cancer type; chemotherapy; chromatin remodeling; clinical application; clinically relevant; combinatorial; effective therapy; experimental study; gene repression; genetic makeup; inhibitor/antagonist; innovation; insight; mouse model; novel; patient derived xenograft model; pre-clinical; precision medicine; prototype; small molecule inhibitor; targeted treatment; therapy outcome

Project Summary ARID1A, encoding a subunit of the SWI/SNF chromatin-remodeling complex, is the most frequently mutated epigenetic regulator across human cancers. Most notably, inactivating mutations in ARID1A occur in ~50% of ovarian clear cell carcinomas (OCCC) and ~30% of ovarian endometrioid carcinomas (OEC). There is an unmet need for effective treatment modalities for ARID1A-mutated ovarian cancers. For example, OCCC is generally refractory to standard agents used to treat epithelial ovarian cancer, and when diagnosed in advanced stages, OCCC carries the worst prognosis of all ovarian cancer subtypes. The overall goal of this proposal is to develop the first combinatorial targeted approach for ARID1A-mutated ovarian cancers with a durable outcome. We show that the inhibition of EZH2 is synthetically lethal with ARID1A mutation. We also show that ARID1A mutation is synthetically lethal with the inhibition of HDAC6. The objectives of this application are to investigate mechanisms underlying this newly discovered synthetic lethality and to investigate a combination therapeutic strategy for ARID1A-mutated ovarian cancer. Our central hypothesis is that targeting EZH2 and HDAC6 using clinically applicable small molecule inhibitors can achieve a durable therapeutic outcome for ARID1A-mutated ovarian cancer. Three Specific Aims are proposed: Aim 1 is to investigate the p53-dependent mechanism by which ARID1A-mutated ovarian cancer cells are selectively sensitive to the inhibition of HDAC6; Aim 2 will investigate the role of the SWI/SNF complex catalytic subunits switch in determining the sensitivity to EZH2 inhibitors in ARID1A-mutated ovarian cancer cells; and Aim 3 will investigate the combinatorial therapeutic strategy for ARID1A-mutated ovarian cancer by simultaneously inhibiting HDAC6 and EZH2. The proposed studies are highly innovative because they challenge current research/clinical paradigms and utilize innovative methods to explore new intervention strategies for ARID1A-mutated ovarian cancers. The research proposed is of high impact because it has the potential to develop the first synthetic lethality-based, combinatorial therapeutic strategy for ARID1A-mutated ovarian cancer with a durable outcome. Since ARID1A is the most frequently mutated epigenetic regulator across human cancers, the mechanistic insights gained from the current studies will have broad implications for many different types of cancers as well.

项目摘要 ARID 1A，编码SWI/SNF染色质重塑复合物的亚基，是最常见的突变， 人类癌症的表观遗传调节因子。最值得注意的是，ARID 1A的失活突变发生在约50%的人中。 卵巢透明细胞癌（OCCC）和约30%的卵巢类上皮癌（OEC）。存在未满足的 对ARID 1A突变卵巢癌的有效治疗方式的需求。例如，OCCC通常 对于用于治疗上皮性卵巢癌的标准药物是难治的，并且当诊断为晚期时， OCCC是所有卵巢癌亚型中预后最差的。该提案的总体目标是发展 这是第一种针对ARID 1A突变卵巢癌的组合靶向方法，具有持久的效果。我们 表明ARID 1A突变对EZH 2的抑制是合成致死的。我们还表明，ARID 1A 突变在HDAC 6的抑制下是合成致死的。本申请的目的是 研究这种新发现的合成致命性的潜在机制， ARID 1A突变卵巢癌的治疗策略。我们的中心假设是，靶向EZH 2和 使用临床适用的小分子抑制剂的HDAC 6可以实现持久的治疗结果， ARID 1A突变卵巢癌本研究提出了三个具体的目的：目的1是研究p53依赖的 ARID 1A突变的卵巢癌细胞对HDAC 6的抑制选择性敏感的机制; 目的2将研究SWI/SNF复合物催化亚基开关在决定对药物敏感性中的作用。 EZH 2抑制剂在ARID 1A突变的卵巢癌细胞中的作用; Aim 3将研究联合治疗 通过同时抑制HDAC 6和EZH 2治疗ARID 1A突变卵巢癌的策略。拟议 这些研究具有高度创新性，因为它们挑战了当前的研究/临床范式，并利用了创新的 方法探索ARID 1A突变卵巢癌的新干预策略。研究提出， 具有很高的影响力，因为它有可能开发出第一种基于合成致命性的组合 ARID 1A突变卵巢癌的治疗策略，具有持久的结果。由于ARID 1A是最 在人类癌症中经常突变的表观遗传调节因子，从目前的研究中获得的机制见解， 这些研究也将对许多不同类型的癌症产生广泛的影响。