New Targeted Therapeutic Approach to Combat Ovarian Cancer
PHILADELPHIA — (Feb. 12, 2018) — According to a new study by The Wistar Institute, EZH2 inhibitors that are currently in clinical development for hematological malignancies and solid tumors may be effectively targeted to epithelial ovarian cancers overexpressing the CARM1 protein. The research was published online in Nature Communications.
Ovarian cancer is the most lethal gynecological malignancy and only limited therapeutic options are currently available. Because of the high genetic heterogeneity of this type of cancer, scientists are working to expand their knowledge of the molecular alterations underlying tumor onset and progression in order to design individualized therapeutic strategies. Results of this new study demonstrated an elevated expression of the CARM1 protein in a set of ovarian cancer tissues compared with normal tissue. CARM1 is a known oncogene in several cancer types, but prior to this study, there were no reports on its role in ovarian cancer.
"Previous studies suggest that direct targeting of CARM1 activity could result in high toxicity," said lead researcher Rugang Zhang, Ph.D., deputy director of The Wistar Institute Cancer Center, professor and co-program leader of the Gene Expression and Regulation Program. "Therefore, we sought to identify an alternative, clinically applicable therapeutic approach for this specific group of patients. We discovered that inhibitors of EZH2 provide an effective strategy to treat ovarian cancers with elevated CARM1 expression."
Zhang and colleagues analyzed a publicly available atlas of ovarian cancer genetic profiles and observed that CARM1 expression is elevated in approximately 20 percent of cases, and it is associated with poor patient survival. Importantly, high CARM1 expression is mutually exclusive with the presence of mutations in BRCA1/2. They also found that small molecule inhibitors of EZH2, which block the EZH2 enzyme and are in clinical development for hematopoietic malignancies, selectively induce arrest of proliferation and cell death in cells with high CARM1 levels and not in cells with normal CARM1 levels.
Mechanistically, the researchers showed that CARM1 regulates the balance between the antagonistic activities of EZH2 and another protein, BAF155. Both these proteins modify the structure of chromatin in specific positions, exerting opposite effects on expression of a common set of target genes that inhibit tumor progression. Causing BAF155 displacement from these targets, CARM1 favors binding of EZH2, which in turn inhibits expression of these antitumor genes, thus favoring tumor progression. The team demonstrated that EZH2 inhibition is an effective strategy to suppress the growth of tumors expressing CARM1 by reactivating these antitumor genes.
The research also included in vivo studies confirming that the EZH2 inhibitor significantly suppressed tumor growth and improved survival in mouse models of ovarian cancer.
"Our study suggests a therapeutic benefit for repurposing a well-tolerated inhibitor with limited toxicity to treat a specific group of ovarian cancer patients with high levels of CARM1 expression," said Sergey Karakashev, Ph.D., first author of the study and a postdoctoral researcher in the Zhang Lab. "Given that CARM1 expression is elevated in other types of cancer, our findings may be extended to a broader array of cancer patients."
This work was supported by National Institutes of Health/National Cancer Institute grants R01CA160331, R01CA163377, R01CA202919, K99CA194318, P01DK68055, and R01DK58185, US Department of Defense OC140632P1 and OC150446. Additional support was provided by an Ovarian Cancer Research Fund Alliance program project and the Mayo Clinic Center for Individualized Medicine. Core support for The Wistar Institute was provided by the Cancer Center Support Grant P30 CA010815.
Co-authors from Wistar include Hengrui Zhu, Shuai Wu, Yuhki Yokoyama, Benjamin G. Bitler, Pyoung-Hwa Park, Andrew V. Kossenkov, and David W. Speicher. Other co-authors include Jeong-Heon Lee, Tamas Ordog, Krutika Satish Gaonkar, and Huihuang Yan from Mayo Clinic, Ronny Drapkin from the University of Pennsylvania, and Jose R. Conejo-Garcia from Moffitt Cancer Center.
The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.