Metabolic basis of ARID1A-mutated 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 对ARID1A突变卵巢癌有效治疗方式的需求尚未得到满足。例如，OCCC是 通常对用于治疗上皮性卵巢癌的标准药物无效，当诊断为 晚期卵巢癌是所有卵巢癌亚型中预后最差的。这个项目的总体目标是 建议开发一种新的ARID1A突变卵巢癌的治疗策略，通过结合 临床适用的代谢性谷氨酰胺酶抑制剂和免疫检查点阻断。我们证明了 ARID1A的失活产生了对谷氨酰胺代谢的依赖。我们还表明，ARID1A 灭活使卵巢癌对抗PD-L1治疗敏感。此应用程序的目标是 研究ARID1A对谷氨酰胺代谢依赖的机制 并探讨ARID1A突变卵巢癌的联合治疗策略。我们的 中心假设是ARID1A突变的卵巢癌可以通过治疗根除 临床适用的谷氨酰胺酶抑制剂如CB-839与抗PD-L1免疫的联合 检查站封锁。提出了两个具体的目标：目标1是研究 ARID1A突变对谷氨酰胺代谢的依赖性；AIM 2将开发一种新的治疗方法 临床适用的谷氨酰胺酶抑制剂联合应用治疗ARID1A突变卵巢癌的研究 抗PD-L1。拟议的研究具有很高的创新性，因为它们挑战了当前的研究/临床 应用创新方法探索ARID1A突变卵巢的新干预策略 癌症。提出的研究具有很高的影响力，因为它将为开发 临床上急需的新型谷氨酰胺酶抑制剂CB- 839和FDA批准的针对ARID1A突变卵巢癌的免疫检查点阻断，这种疾病 目前还没有有效的治疗方法。由于ARID1A是最频繁突变的表观遗传调控因子 从目前的研究中获得的机械论见解将对许多人产生广泛的影响 还有不同类型的癌症。

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.