Metabolic Approaches for ARID1A-Mutated Ovarian Cancer
Abstract
Rationale and Objective: Epithelial ovarian cancer (EOC) carries a grim prognosis, with only 30% of patients with this disease living for 5 years or more. Among all EOC subtypes, ovarian clear cell carcinoma (OCCC) carries the worst prognosis when diagnosed at an advanced stage. The gene ARID1A is the highest mutated gene in OCCC that occurs in over 50% of the cases and is a known driver mutation in OCCC. In addition, ARID1A is mutated in ~30% of endometrioid subtype of EOCs. In the current application, we discovered that inhibition of a key metabolic enzyme called glutaminase is more effective in ARID1A-mutated ovarian cancer. Recent published work and our own studies showed that an immunological checkpoint blockade therapy known as anti-PD-L1 antibody is also effective against ARID1A-mutated ovarian cancers. Interestingly, there is evidence to suggest that glutaminase inhibitors can potentially boost the effects of anti-PD-L1 immunological therapy. Notably, anti-PD-L1 immunotherapy is Food and Drug Administration (FDA)-approved, and therapeutic reagents against glutaminase enzymatic activity are now in clinical development for other diseases. They are very well tolerated in clinic. These features of the anti-PD-L1 therapy and the glutaminase inhibitor make them ideal for developing novel ovarian cancer therapeutics that depend on the ARID1A mutational status, the very definition of precision medicine. In this application, we will study how we could explore the clinical utility of PD-L1 and glutaminase-inhibiting agents in ARID1A-mutated ovarian cancer. Our proposal consists of two aims. First, we will investigate how the ARID1A mutation confers sensitivity to glutaminase inhibition. Second, we will investigate whether glutaminase and PD-L1 targeting agents can be developed as novel therapeutic approaches for ARID1A-mutated ovarian cancer in preclinical models. Taken together, the objective of the proposed studies is to develop the first effective therapeutic strategies by targeting glutaminase and PD-L1 using clinically applicable agents in a personalized manner for ARID1A-mutated ovarian cancer. Impact and Ultimate Applicability: We anticipate that this work could benefit patients with ovarian cancer by developing urgently needed therapeutics based on ARID1A mutational status. The ideal outcome would be that a combination of the PD-L1 antibody and the glutaminase inhibitors could be used to eradicate ARID1A-mutated ovarian cancer. In the immediate short term, the proposed studies will provide fundamental mechanistic insights into the role of ARID1A mutation in regulating the metabolic reprogramming in ovarian cancer. In the long term, they will lay the critical foundation for developing a novel combinatory intervention strategy for ARID1A-mutated ovarian cancer. Notably, the glutaminase inhibitor CB-839 is now in clinical development for other cancer types, and anti-PD-L1 is FDA-approved. Thus, they are readily available for a novel clinical application in ARID1A-mutated ovarian cancer. Given the growing body of knowledge on PD-L1 and glutaminase inhibitors, we believe that these inhibitors represent promising new therapeutic agents for ARID1A-mutated ovarian cancer that merit further study as outlined in this application. The impact of the proposed studies on ovarian cancer is very high because this could lead to the first effective strategies for treating ARID1A-mutated ovarian cancer by repurposing existing drugs against PD-L1 and glutaminase. If successful, these studies will truly have a transformative impact for the management of ARID1A-mutated ovarian cancer for female Service members, Veterans, retirees, their family members, and of course all women impacted by this disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010140
Entities
People
- Rugang Zhang
Organizations
- United States Army
- Wistar Institute