Therapeutic Targeting of Mevalonate Pathway in 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 a known driver mutation in OCCC. In addition, ARID1A is mutated in ~30% of the endometrioid subtype of EOCs. In the current application, we discovered that the inhibitors of a key metabolic pathway called mevalonate pathway are 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, statins induce a form of cell death known as pyroptosis that can boost the anti-tumor effect of the immune checkpoint blockade therapy. Notably, both anti-PD-L1 immunotherapy and mevalonate pathway inhibitor statins are FDA-approved. They are very well tolerated in the clinic. These features of the anti-PD-L1 therapy and statins 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 mevalonate pathway inhibiting agents in ARID1A-mutated ovarian cancer. Our proposal consists of two aims. First, we will investigate how the ARID1A mutation confers sensitivity to the inhibition of the mevalonate pathway. Second, we will investigate whether statins 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 the mevalonate pathway and PD-L1 repurposing FDA-approved, 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 statins 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 mevalonate pathway 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, both statins and anti-PD-L1 are 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 statins, we believe that these inhibitors represent promising new therapeutic agents for ARID1A-mutated ovarian cancer that merits 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 mevalonate pathway. 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 devastating disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210156
Entities
People
- Rugang Zhang
Organizations
- United States Army
- Wistar Institute