Synthetic lethality based combination approaches to ARID1A mutation in ovarian cancer

项目摘要 ARID1A编码SWI/SNF染色质重塑复合体的一个亚单位，是最频繁的突变 人类癌症的表观遗传调控。最值得注意的是，ARID1A的失活突变发生在约50%的 卵巢透明细胞癌(OCCC)和卵巢子宫内膜样癌(OEC)约占30%。有一个未满足的人 ARID1A基因突变的卵巢癌需要有效的治疗方式。例如，OCCC通常是 对用于治疗上皮性卵巢癌的标准药物无效，当诊断为晚期时， OCCC是所有卵巢癌亚型中预后最差的。这项提议的总体目标是发展 首个针对ARID1A突变卵巢癌的组合靶向治疗方法，具有持久的结果。我们 表明抑制EZH2对ARID1A突变具有综合致死性。我们还表明，ARID1A 在HDAC6的抑制下，突变是综合致命的。此应用程序的目标是 研究这种新发现的合成致命性的潜在机制，并研究一种组合 ARID1A突变卵巢癌的治疗策略。我们的中心假设是瞄准EZH2和 使用临床适用的小分子抑制剂的HDAC6可以达到持久的治疗效果 ARID1A基因突变的卵巢癌。提出了三个具体的目标：目标1是研究P53依赖的 ARID1A突变的卵巢癌细胞对HDAC6抑制选择性敏感的机制； 目的2将研究SWI/SNF复合催化亚基开关在决定对 ARID1A突变卵巢癌细胞中的EZH2抑制剂；Aim 3将研究联合治疗 同时抑制HDAC6和EZH2治疗ARID1A突变卵巢癌的策略。建议数 研究是高度创新的，因为它们挑战当前的研究/临床范式，并利用创新 方法探索ARID1A突变卵巢癌新的干预策略。这项研究建议 影响很大，因为它有可能开发出第一个基于合成致命性的、组合的 ARID1A突变卵巢癌的治疗策略具有持久的结果。因为ARID1A是最多的 人类癌症中频繁突变的表观遗传调控因子，从当前获得的机制洞察力 研究也将对许多不同类型的癌症产生广泛的影响。

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.