Synthetic Lethal Therapeutic Approaches for ARID1A-Mutated Ovarian Cancer
Technical Report,30 Sep 2016,29 Sep 2017
The Wistar Institute of Anatomy and Biology Philadelphia United States
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Epithelial ovarian cancer EOC is the leading cause of death among gynecological malignancies in the United States. Among all EOC subtypes, ovarian clear cell carcinoma OCCC carries the worst prognosis when diagnosed at an advanced stage, and there is currently no effective therapy for this disease. The gene ARID1A, which encodes a subunit of the epigenetic SWISNF chromatin-remodeling complex, is the highest mutated gene in OCCC that occurs in over 50 percent of the cases. In addition, ARID1A is also mutated in approximately 30 percent of endometrioid subtype of EOC. Since ARID1A is the highest mutated gene and a known driver mutation in OCCC, we performed an unbiased screen and demonstrated that in ARID1A-mutated OCCC the inhibition of EZH2, another epigenetic regulator, is synthetically lethal. In addition to EZH2, our unexplored data suggest that ARID1A-mutated ovarian cancer cells are also selectively sensitive to the inhibition of HDAC6. Our central hypothesis is that ARID1A-mutated ovarian cancers can be treated and ultimately eradicated based on the synthetic lethality through targeting EZH2 and HDAC6 using clinically applicable small molecule inhibitors. The objective of this proposal is to develop first effective targeted therapeutic approach for ARID1A-mutated ovarian cancers.
- Medicine and Medical Research