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: 10443547
• 负责人: Rugang Zhang
• 金额: $ 12.74万
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443547
• 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; 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 ARID1A编码SWI/SNF染色质复合物的亚基是最常见的突变 人类癌症的表观遗传调节剂。最值得注意的是，ARID1A中的灭活突变发生在〜50％ 卵巢透明细胞癌（OCCC）和约30％的卵巢子宫内膜类癌（OEC）。有一个未满足的 需要有效的ARID1A突变卵巢癌的治疗方式。例如，OCCC通常是 对用于治疗上皮卵巢癌的标准药物的难治性，当在晚期诊断时， OCCC具有所有卵巢癌亚型的最差预后。该提议的总体目标是发展 ARID1A突变的卵巢癌的第一种组合靶向方法具有持久的结果。我们 表明对EZH2的抑制作用在合成中具有致命的ARID1A突变。我们还表明Arid1a 突变在抑制HDAC6的情况下是致命的。此应用程序的目标是 研究这种新发现的合成杀伤力并研究组合的机制 ARID1A突变的卵巢癌的治疗策略。我们的中心假设是针对EZH2和 使用临床上适用的小分子抑制剂的HDAC6可以实现持久的治疗结果 ARID1A突变的卵巢癌。提出了三个具体目标：目标1是研究依赖p53 ARID1A突变的卵巢癌细胞对HDAC6的抑制选择性敏感的机制； AIM 2将研究SWI/SNF复合物催化亚基的作用在确定对 ARID1A突变的卵巢癌细胞中的EZH2抑制剂； AIM 3将研究组合治疗 通过同时抑制HDAC6和EZH2的ARID1A突变卵巢癌的策略。提议 研究具有很高的创新性，因为它们挑战了当前的研究/临床范例并利用创新性 探索ARID1A突变卵巢癌的新干预策略的方法。研究提出了 具有很高的影响，因为它有可能开发第一个基于合成致死性的组合物 ARID1A突变的卵巢癌的治疗策略具有持久的结果。由于Arid1a是最大的 经常突变的表观遗传调节剂在人类癌症中，从电流中获得的机械见解 研究也将对许多不同类型的癌症具有广泛的影响。