Metabolic basis of ARID1A-mutated ovarian cancer

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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.