Mouse Study Reveals Potential Combination Therapy for Ovarian Cancer

Mouse Study Reveals Potential Combination Therapy for Ovarian Cancer

Researchers at the Johns Hopkins Kimmel Cancer Center have discovered a combination therapy that may hold promise in halting ovarian cancer progression. The combination of epigenetic therapy and immunotherapy reduced tumor burden and extended survival in a mouse model of epithelial ovarian cancer (EOC).

The study, “Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden,” was published in the journal Proceedings of the National Academy of Sciences.

Global epigenetic changes, which prevent genes from being expressed, are considered a hallmark of cancer. Epigenetics involves mechanisms that influence gene expression without altering the underlying DNA sequence.

Recruitment of epigenetic modifiers such as DNA methyl transferases (DNMT) and histone deacetylases (HDACs) is known to be important to maintain cancer-epigenetic changes. Therefore, epigenetic therapy targets the epigenetic abnormalities of cancer mainly through several DNMT and HDAC inhibitors.

A class of immunotherapy drugs known as checkpoint inhibitors help the immune system recognize and attack cancer cells. Although epigenetic therapy and immunotherapy were shown to be efficient treatments for some types of cancer, ovarian cancer does not respond successfully to either of these therapies.

Previous data from the research team suggested that epigenetic drugs boost the immune system, potentially improving patients’ responses to immunotherapy.

“We’ve taken two types of therapies that aren’t very effective in ovarian cancer and put them together to make them better at revving up the immune system and attacking the tumor,” Cynthia Zahnow, PhD, the senior author of the study, said in a press release.

Researchers found that treatment with the DNMT inhibitor (DNMTi) 5-azacytidine (AZA) increased the immune response against the tumor, reducing tumor burden and extending survival in a mouse model of EOC.

The AZA treatment, combined with an HDAC inhibitor (HDACi), improved the immune response even more, as well as the survival of the mice.

The boost of immune response to cancer was found to be linked to type 1 interferon (IFN) signaling. Type 1 IFN is involved in the regulation of the immune system, including defense against viruses.

The best anti-tumor effect and longest overall survival, however, was achieved when the mice were treated with a triple combination of AZA/HDACi and an anti-PD-1 immune checkpoint inhibitor.

“We think that AZA and the HDACis are bringing the soldiers, or immune cells, to the battle. But the checkpoint inhibitor is giving them the weapons to fight,” Zahnow added.

“Combining epigenetic therapy and a checkpoint blocker leads to the greatest reduction in tumor burden and increase in survival in our mouse model and may hold the greatest promise for our patients,” she concluded.

Ongoing clinical trials (NCT02900560 and NCT02811497) are testing the effectiveness of the combination of AZA and checkpoint inhibitors to treat ovarian cancer. The addition of an HDACi to this combination therapy may be evaluated in future clinical trials.

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