New Therapeutic Target Identified for Ovarian Cancer Subtype

Rugang Zhang, PhD

Inhibiting EZH2 may improve outcomes in patients with clear cell ovarian carcinoma who harbor a ARID1A mutation. The findings, which were published online in Nature Medicine by researchers at The Wistar Institute, are notable because response rates to standard platinum-based chemotherapy are low among patients with clear cell ovarian cancer, necessitating new therapeutic targets.

“One of the significant challenges with the treatment of ovarian cancer is finding a suitable target that effectively halts the progression of the disease in a personalized manner based on one’s genetic makeup,” said Rugang Zhang, PhD, associate professor, Wistar’s Gene Expression and Regulation Program, and corresponding author of the study, in a press release. “With this study, we have done just that. For patients with this particular subtype, this newly discovered targeted approach may eventually lead to the first effective targeted therapy they’ve ever had.”

The enzyme EZH2 facilitates compaction of DNA in the chromatin structure. Although a certain level of EZH2 is important for maintaining a transcriptional balance, an overabundance of this enzyme turns off the genes in the compacted regions, stopping the cells from receiving the DNA instructions necessary for making tumor-fighting proteins. Studies have shown an overabundance of EZH2 to be associated with progression of numerous cancers, including ovarian clear cell carcinoma, a cancer that affects 5% to 10% of US women with ovarian cancer.

Zhang et al examined the relationship between EZH2 and ARID1A, a gene that remodels chromatin. When ARID1A is normally functioning, it enables chromatin to unfold so that cells receive signals that dictate their behavior. This is necessary for preventing cells from becoming cancerous.

Using experimental models, the researchers found that EZH2 inhibition led to regression of ovarian tumors with mutated ARID1A. Furthermore, there were minimal effects on the growth of ovarian tumors with normal or unmutated ARID1A. Based on these findings, Zhang and colleagues concluded that the response to EZH2 inhibition correlates with ARID1A mutational status.

“Excitingly, this study provides a much-needed therapeutic strategy for clear cell ovarian cancer and can be utilized to aid in the identification of patients that could benefit from EZH2 inhibition therapy,” said Benjamin Bitler, PhD, an American Cancer Society postdoctoral fellowship recipient and first author of the study, in a statement.

The researchers believe their findings have the potential to change the care of many patients with ovarian clear cell carcinomas, since 50% of women with these cancers have been found to have ARID1A mutations. In fact, Zhang et al note that ARID1A has one of the highest mutation rates among all types of human cancer, yet no therapies designed to target this common mutation have been developed to date. EZH2 inhibitors are, however, in development for other cancer types, most notably B-cell lymphomas.

“With EZH2 inhibitors currently in clinical development, we believe that our findings will have far-reaching implications,” said Bitler.

Bitler BG, Aird KM, Garipov A, et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers [published online February 16, 2015]. Nat Med. doi:10.1038/nm.3799.