Novel Combination Strategy to Expand PARP Inhibitors for Ovarian Cancer Treatment

PHILADELPHIA — (Jan. 30, 2020) — Combining EZH2 inhibition and PARP1 inhibition may provide a new therapeutic strategy for ovarian cancers that have functional DNA damage repair and thus would not typically respond to PARP inhibitor treatment alone. According to a study by The Wistar Institute, in epithelial ovarian cancers characterized by overexpression of the CARM1 oncogene, EZH2 inhibitors can shift the equilibrium between different DNA damage repair pathways in a way that renders cancer cells vulnerable to PARP inhibitors. These results were published online in Cancer Cell.

High-grade serous ovarian cancer (HGSOC) is the most common and lethal type of ovarian cancer. PARP inhibitors have recently been approved for maintenance of HGSOC following platinum-based chemotherapy, but their use is limited to specific subtypes that have defects in a DNA repair pathway called homologous recombination (HR).

“Despite high response rates in a subset of patients, right now PARP inhibitors are not for everyone,” 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. “Expanding the use of these new drugs represents a major unmet clinical need as it would affect a large population of ovarian cancer patients that do not currently benefit from PARP inhibitors and possibly those who develop resistance to the treatment.”

PARP inhibitors work by hindering certain DNA repair processes. Cancer cells that accumulate excessive DNA damage will die. However, this approach is most effective in cancer cells that have a defect in HR, an error-free mechanism that repairs DNA breaks, whereas HR-proficient cancers are not sensitive to treatment.

Zhang and colleagues wanted to find a way to sensitize this group of cancers through a combinatorial approach. Previous research in the Zhang lab has demonstrated the oncogenic role of the CARM1 gene that is amplified in a set of ovarian cancers and showed that in these cancers, inhibitors of the EZH2 enzyme are an effective treatment.

In this study, the authors tested the effects of combining PARP and EZH2 inhibition and observed that the EZH2 inhibitor enhanced the cytotoxic effect of the PARP inhibitor in cancer cells with functional HR, but only in the presence of elevated CARM1 expression, suggesting that this effect is dependent on the expression level of CARM1.

Mechanistically, elevated CARM1 expression results in transcriptional silencing of the MAD2L2 gene by EZH2. MAD2L2 activates a DNA repair pathway called non-homologous end joining (NHEJ) that is an error-prone mechanism alternative to HR. Therefore, EZH2 inhibition relieves MAD2L2 expression and shifts the choice of DNA repair process towards NHEJ, even in the presence of functional HR.

As a consequence of repairing DNA damage via a low-fidelity mechanism, cancer cells accumulate unrepaired DNA breaks and chromosomal abnormalities, which ultimately leads to mitotic catastrophe, a mode of cell death that occurs when cells with a heavily damaged genome try to divide.

“Based on our findings, we propose a combinatorial approach using EZH2 inhibitors and PARP inhibitors as a precision treatment strategy for patients whose cancer has an elevated expression of CARM1 and functional HR DNA repair mechanism, including those who developed resistance to PARP inhibitors,” said Sergey Karakashev, Ph.D., first author of the study and a postdoctoral researcher in the Zhang Lab.

This approach was tested in vivo in different mouse models of epithelial ovarian cancer with high CARM1 levels, confirming that the combination of inhibitors was significantly more effective in suppressing tumor growth and improving survival compared with either inhibitor alone.
No toxic effects were observed, suggesting that the combination treatment was well tolerated.

“Notably, CARM1 is often overexpressed in several cancer types, therefore our discovery may have broader implications expanding the clinical use of PARP inhibitors for cancer treatment,” said Zhang.

Co-authors: Takeshi Fukumoto, Bo Zhao, Jianhuang Lin, Shuai Wu, Nail Fatkhutdinov, Pyoung-Hwa Park, Galina Semenova, Andrew V. Kossenkov, and Qin Liu from Wistar; Stephanie Jean, Mark G. Cadungog and Mark E. Borowsky from Helen F. Graham Cancer Center & Research Institute.

Work supported by: National Institutes of Health (NIH) grants R01CA160331, R01CA163377, R01CA202919, R01CA239128, P50CA228991, and R50CA211199; U.S. Department of Defense grants OC150446 and OC180109. Additional support was provided by The Honorable Tina Brozman Foundation for Ovarian Cancer Research (Tina’s Wish) and The Tina Brozman Ovarian Cancer Research Consortium 2.0, Ovarian Cancer Research Alliance (Collaborative Research Development Grant and Ann and Sol Schreiber Mentored Investigator Award), and 2018 AACR-AstraZeneca Ovarian Cancer Research Fellowship to the first author. Core support for The Wistar Institute was provided by the Cancer Center Support Grant P30CA010815.

Publication information: EZH2 inhibition sensitizes CARM1-high, homologous recombination proficient ovarian cancers to PARP inhibition, Cancer Cell, 2020. Online publication.

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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.