Response rates to standard platinum-based chemotherapy among patients with the clear cell subtype of ovarian cancer are especially low, necessitating new treatment targets.
Rugang Zhang, PhD
Response rates to standard platinum-based chemotherapy among patients with the clear cell subtype of ovarian cancer are especially low, necessitating new treatment targets. Researchers at The Wistar Institute in Philadelphia, Pennsylvania, have announced that they may have identified one such target, opening the door to the development of the first targeted therapy for patients with ovarian clear cell carcinomas. The study findings were published online inNature Medicine.
“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 Wistar 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.”
Zhang et al studiedARID1A, a gene that remodels chromatin, a complex of proteins that enables DNA to be tightly packed within cells. Normally functioningARID1Aenables chromatin to unfold so that cells receive signals that dictate their behavior, which is important for preventing cells from becoming cancerous. In particular, the researchers examined howARID1Aaffects EZH2, an enzyme that 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.
The relationship betweenARID1Aand EZH led the researchers to explore EZH2 inhibition as a potential treatment target. Using experimental models, they found that EZH2 inhibition caused regression of ovarian tumors with mutatedARID1A. Furthermore, there were minimal effects on the growth of ovarian tumors with normal or unmutatedARID1A. Based on these findings, Zhang and colleagues concluded that the response to EZH2 inhibition correlates withARID1Amutational status.
Zhang and colleagues believe their research has the potential to change the care of many patients with ovarian clear cell carcinomas, because 50% of women with these cancers have been found to haveARID1Amutations. In fact, Zhang et al note thatARID1Ahas 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. However, EZH2 inhibitors are 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 Benjamin Bitler, PhD, an American Cancer Society postdoctoral fellowship recipient and first author of the study, in the press release. “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.”
Bitler BG, Aird KM, Garipov A, et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers.Nat Med