Immunological Approaches for ARID1A-Mutated Ovarian Cancer
Abstract
Rationale and Objectives 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. Using an unbiased screen, we discovered that immunological checkpoint blockade therapy, known as anti-PD-L1 antibody, is more effective in ARID1A-mutated ovarian cancer. Our recent published work showed that an inhibitor to HDAC6 is also effective against ARID1A-mutated ovarian cancers. Interestingly, our unpublished preliminary data indicate that HDAC6 inhibitors can potentially boost the effects of anti-PD-L1 immunological therapy.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 HDAC6 are now in clinical development for other diseases. They are very well tolerated in clinic. These features of anti-PD-L1 therapy and HDAC6 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 HDAC6 inhibiting agents in ARID1A-mutated ovarian cancer. Our proposal consists of two aims. First, we will investigate how HDAC6 inhibition and ARID1A status affects tumor immune microenvironment. Second, we will investigate whether PD-L1 and HDAC6 targeting agents can be developed as novel therapeutic approaches for ARID1A-muated ovarian cancer in preclinical models. Taken together, the objective of the proposed studies is to develop the first effective therapeutic strategies by targeting PD-L1 and HDAC6 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 PD-L1 antibody and HDAC6 inhibitors could be used to fully eradicate ARID1A-mutated ovarian cancer. In the immediate short term, the proposed studies will provide fundamental mechanistic insights into the role of ARID1A mutation and HDAC6 inhibition on the tumor immune microenvironment 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, HDAC6 inhibitor ACY1215 is now in clinical development for other cancer types, and anti-PD-L1 is FDA-approved. Thus, they are readily available for novel clinical application in ARID1A-mutated ovarian cancer. Given our recent published results and the growing body of knowledge on PD-L1 and HDAC6, we believe that these inhibitors represent promising new therapeutic agents for ARID1A-mutated ovarian cancer that merits the further study outlined in this application. The impact of the proposed studies on ovarian cancer is very high because this could lead to the first effective strategy for treating ARID1A-mutated ovarian cancer by repurposing existing drugs against PD-L1 and HDAC6.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910154
Entities
People
- Rugang Zhang
Organizations
- United States Army
- Wistar Institute