Synthetic Lethal Therapeutic 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. This is largely due to (1) lack of effective treatment options for this disease and (2) poor understanding of the biological insights into the disease. 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 the survival of the ARID1A-mutated OCCC depends on the activity of two enzymes, namely EZH2 and HDAC6. Notably, therapeutic reagents against both EZH2 and HDAC6 are now in clinical development for other diseases. They are very well tolerated in the clinic. These features of EZH2 and HDAC6 make them ideal targets 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 EZH2 and HDAC6-inhibiting agents in ARID1A-mutated ovarian cancer. Our proposal consists of two aims. First, we will investigate how EZH2 and HDAC6 cooperate in selectively eliminating ARID1A-mutated ovarian cancer cells. Second, we will investigate whether EZH2 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 EZH2 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 EZH2 and HDAC6 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 ovarian cancer. In the long term, they will lay the critical foundation for developing epigenetic-based small molecule intervention strategies for ARID1A-mutated ovarian cancer. Notably, EZH2 and HDAC6 targeting drugs have recently been developed and are ready for clinical trials. However, the potential clinical utility of this new class of drugs in EOC has not been explored. If successful, the proposed studies would quickly lead in turn to the development of EZH2 and HDAC6 inhibitors as novel therapeutics for ARID1A-mutated ovarian cancer. Given our recent published results and the growing body of knowledge on EZH2 and HDAC6, we believe that these inhibitors represent promising new therapeutic agents for ARID1A-mutated ovarian cancer that merits the 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 EZH2 and HDAC6.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610496
Entities
People
- Rugang Zhang
Organizations
- United States Army
- Wistar Institute