SWCRF supported research at Johns Hopkins discovers potential combination therapy for ovarian cancer patients

 

Cynthia Zahnow, PhD

Research at Johns Hopkins Kimmel Cancer Center supported in part by donations to the SWCRF has launched a clinical trial for a combination therapy for ovarian cancer that harnesses the power of epigenetic drugs and the immune system against cancer cells. 

Findings from a study published last month in the Proceedings of the National Academy of Sciences by SWCRF grantee Cynthia Zahnow, Ph.D. and her collaborators Meredith Stone, Ph.D. and Kate Chiappinelli, Ph.D. demonstrated that lab mice with ovarian cancer who received drugs to reactivate dormant genes along with other drugs that activate the immune system had a greater reduction of tumor burden and significantly longer survival than those who received any of these drugs alone. 

The findings could lead to a new way to attack ovarian cancer by strengthening the body’s natural immune response against these tumors. Ovarian cancer is currently the leading cause of death from gynecological malignancies in the U.S. The National Cancer Institute projected that there would be 22,440 new cases of ovarian cancer diagnosed in 2017 and that more than 14,000 women would die from the disease in the year. 

“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,” said Cynthia Zahnow, Ph.D., associate professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Immunotherapy drugs known as checkpoint inhibitors, which help the immune system recognize cancers and fight them off, have shown success in treating melanoma, non-small cell lung cancer, and renal cell cancers. However, these therapies have had only modest effects on ovarian cancer. 

Similarly, epigenetic drugs  have been used to treat some types of cancer by turning on genes that have been silenced either by the presence of chemical tags, known as methyl groups, or by being wound too tightly around protein spools known as histones—but these drugs haven’t been effective against ovarian cancer either. 

Zahnow and her colleagues were inspired to investigate a new way to treat ovarian cancer by two recent publications from their group, showing that epigenetic drugs turn on immune signaling in ovarian, breast, and colon cancer and that these immune genes are activated when epigenetic therapy turns on segments of ancient retroviruses that activate certain protein signaling in the cells.  The collaborators wanted to know if this increase in immune signaling could lead to the recruitment of tumor killing immune cells to the cancer.                 

The Study Approach 

The research involved injecting mouse ovarian cancer cells into the animals’ abdomens to mimic human disease. These cells eventually developed into hundreds of small tumors, which caused fluid to collect within the abdomen, a condition known as ascites. Floating in this fluid were a milieu of both cancer and immune cells, Zahnow explained, offering a convenient way to keep tabs on both the tumor and the animals’ immune response. 

The researchers started by pretreating the ovarian cancer cells outside of the mouse in a culture dish with an inhibitor drug called 5-azacytidine, or AZA, that  knocks methyl groups from DNA. After injecting these cells into mice, the researchers found that animals who had received the pretreated cells had significantly decreased ascites or tumor burden, and significantly more cancer-fighting immune cells in the ascites fluid compared to those injected with untreated cells. These cells also had increased activity in a variety of genes related to immune response. Pretreating these cells with HDACis, inhibitors that help DNA uncoil from histones, didn’t affect the animals’ ascites or boost their immune response. 

These early findings suggested that changes in gene activity induced by AZA cause the tumor cells themselves to summon immune cells to their location. In addition, when the researchers transplanted untreated cells into mice and treated the animals with both AZA and an HDACi, significantly more immune cells were in the ascites fluid, suggesting that the HDACi seemed to be acting on the animals’ immune systems. These animals also had decreased ascites, lower tumor burden, and longer survival than animals who received just AZA. 

A Combined Effort 

When the researchers treated the mice with both AZA and an HDACi, along with an immune checkpoint inhibitor, which can activate the immune system, they got the greatest response: the highest decreases in ascites and tumor burden, and the longest survival. Further experiments using mice with compromised immune systems showed that the immune system is pivotal to the action of these drugs, rather than the drugs themselves acting directly to kill tumor cells. 

“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,” said Zahnow, who also worked closely on the project with SWCRF grantee Stephen Baylin, M.D. 

The clinical trial launched by this preclinical data started enrolling patients in December 2016  and is testing the effectiveness of combining AZA and a checkpoint inhibitor.  Future trials may add in an HDACi to determine if it affects outcomes. 

In addition to Zahnow, Stone and Chiappinelli, other scientists who participated in this study include Huili Li, Lauren M. Murphy, Meghan E. Travers, Michael J. Topper, Dimitrios Mathios, Michael Lim, Ie-Ming Shih, Tian-Li Wang Chien-Fu Hung, and Stephen B. Baylin of Johns Hopkins; Vipul Bhargava, Karla R. Weihagen, Glenn Cowley, and Kurtis E. Bachman of Janssen Research & Development; and Reiner Strick and Pamela L. Strissel of University-Clinic Erlangen.

 

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