Metabolic basis of ARID1A-mutated ovarian cancer

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）。有一个 对ARID 1A突变卵巢癌的有效治疗方式的未满足的需求。例如，OCCC是 通常对用于治疗上皮性卵巢癌的标准药物是难治的，并且当被诊断为 晚期，OCCC携带所有卵巢癌亚型中最差的预后。这个项目的总体目标是 一项新的研究建议是开发一种新的ARID 1A突变卵巢癌的治疗策略， 具有免疫检查点阻断的临床上可应用的代谢转氨酶抑制剂。我们证明了 ARID 1A失活产生对谷氨酰胺代谢的依赖性。我们还表明，ARID 1A 灭活使卵巢癌对抗PD-L1治疗敏感。本申请的目的是 研究ARID 1A产生的谷氨酰胺代谢依赖性的潜在机制 失活，并研究ARID 1A突变卵巢癌的联合治疗策略。我们 中心假设是ARID 1A突变的卵巢癌可以通过治疗根除。 临床上适用的转氨酶抑制剂如CB-839和抗PD-L1免疫抑制剂的组合 检查站封锁。提出了两个具体的目的：目的1是研究潜在的机制， ARID 1A突变对谷氨酰胺代谢的依赖性;目标2将开发一种新的治疗方法 通过联合临床上可应用的转氨酶抑制剂和 抗PD-L1抗体拟议的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，并利用创新方法探索ARID 1A突变卵巢癌的新干预策略 癌的这项研究具有很高的影响力，因为它将为开发 迫切需要的新的治疗策略，通过重新利用临床上适用的转氨酶抑制剂CB- 839和FDA批准的ARID 1A突变卵巢癌的免疫检查点阻断， 目前还没有有效的治疗方法。由于ARID 1A是最频繁突变的表观遗传调节因子， 人类癌症，从目前的研究中获得的机制见解将对许多人产生广泛的影响。 不同类型的癌症。

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 a novel therapeutic strategy for ARID1A-mutated ovarian cancers by combining a clinically applicable metabolic glutaminase inhibitor with an immune checkpoint blockade. We show that the ARID1A inactivation creates a dependence on the glutamine metabolism. We also show that ARID1A inactivation sensitizes ovarian cancer to anti-PD-L1 treatment. The objectives of this application are to investigate the mechanisms underlying the dependence on the glutamine metabolism created by ARID1A inactivation and to investigate a combination therapeutic strategy for ARID1A-mutated ovarian cancer. Our central hypothesis is that ARID1A-mutated ovarian cancer can be therapeutically eradicated by the combination of a clinically applicable glutaminase inhibitor such as CB-839 and an anti-PD-L1 immune checkpoint blockade. Two Specific Aims are proposed: Aim 1 is to investigate the mechanism underlying the dependence of ARID1A mutation on the glutamine metabolism; and Aim 2 will develop a novel therapeutic approach for ARID1A-mutated ovarian cancer by combining a clinically applicable glutaminase inhibitor and anti-PD-L1. 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 will provide a scientific rationale for developing urgently needed novel therapeutic strategies by repurposing the clinically applicable glutaminase inhibitor CB- 839 and an FDA-approved immune checkpoint blockade for ARID1A-mutated ovarian cancer, a disease that currently has no effective therapy. 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.