The Combination Strategy May Hold Promise for Ovarian Cancer

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Johns Hopkins Kimmel Cancer Center The researchers showed that mice with ovarian cancer who received drugs to activate sleepless genes along with other drugs that activate the immune system had a greater reduction in tumor weight and more live longer than those who received any medications alone.

The study prompted a clinical trial in ovarian cancer patients. The investigators, led by graduate student Meredith Stone, Ph.D. with postdoctoral Kate Chiappinelli, Ph.D .; and senior author Cynthia Zahnow, Ph.D., believes it could lead to a new way to attack ovarian cancer by strengthening the body’s natural resistance against these tumors. It was published in the December 4, 2017, issue of Methods of the National Academy of Science.

Ovarian cancer is now the leading cause of death from gynecological diseases in the U.S. “We took two different therapies that were less effective on ovarian cancer and combined them to cure them to change the immune system and tumor attack, ”said Zahnow, associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.

Zahnow said a class of immunotherapy drugs known as checkpoint inhibitors, which are currently being studied by Bloomberg ~ Kimmel Institute for Cancer Immunotherapy, can help the immune system recognize cancers and fight them. Drugs have been shown to be successful in the treatment of melanoma, nonsmall cell lung cancer and kidney bladder cancer, but their effect on ovarian cancer is limited.

Similarly, another class of drugs known as epigenetic therapies have been used to treat certain types of cancer by mutating genes that have been silenced — even with the advent of chemical tags, known to methyl groups, or by sticking to the wound surrounding protein spools, are known as histones – but these drugs are not effective against ovarian cancer.

Zahnow and his colleagues were inspired to investigate a new way to treat ovarian cancer through two published publications from their group showing that epigenetic medicine unlocks the immune. signaling of ovarian, breast and colon cancer cells (Li et al., Oncotarget 2014). These immune genes are activated when epigenetic therapy opens up parts of ancient retroviruses that activate type 1 interferon signaling in cells (Chiappinelli et al., Cell 2015). Stone, Chiappinelli and Zahnow want to know if this increase in immune signaling could lead to tumor recruitment that kills cancer immune cells.

Zahnow and his colleagues worked with a mouse model of the disease in which mouse ovarian cancer cells were injected into the stomach of animals to mimic human disease. These cells eventually become hundreds of small tumors, causing fluid to collect in the abdomen, a condition known as ascites. Floating this fluid is a milieu in both cancer and immune cells, offering a convenient way to keep tabs on both tumor and immune response in animals.

The researchers started by pretreating ovarian cancer cells outside the animal in a culture dish with a DNA methyltransferase inhibitor (a drug that extracts methyl groups from DNA) called 5 -azacytidine (AZA). After injecting these cells into mice, the researchers found that animals that received purchased cells significantly reduced ascite or tumor weight and were more likely to fight cancer immune systems. cells in ascites fluid versus injected untreated cells. These cells also have increased activity of various genes associated with the resistance response. Enlargement of these cells using histone deacetylase inhibitors (HDACis), which help detect DNA from histones, did not affect the ascites of animals or increase their resistance response.

These early studies suggested that changes in AZA-induced gene activity cause tumor cells themselves to summon immune cells to their location. In addition, when the researchers transplanted untreated cells into mice and treated animals with both AZA and an HDACi, more immune cells were present in the ascites fluid, suggesting that the HDACi acts on the immune systems of animals. Mice also had reduced ascites, shorter tumor weight and longer survival than mice that received AZA alone.

When the researchers treated mice with both AZA and an HDACi, along with an immune checkpoint inhibitor, they elicited the most response-the highest reduction in ascites and weight gain. tumor, and the longest to live. Further experiments using immunocompromised immunity have shown that the immune system is more important in the action of these drugs, than the drugs themselves that act directly to kill tumor cells.

“We think AZA and HDACis bring soldiers, or immune cells, into battle. But the checkpoint deterrent gives them weapons to fight,” said Zahnow, who also collaborated with epigenetics scientist Stephen Baylin, MD, on this project.

The preclinical data generated by this study have already been used to assist patients with ovarian cancer through ongoing clinical trials to test the effectiveness of combining AZA and a checkpoint inhibitor. Future trials may add an HDACi to determine if this affects outcomes.

“Combining epigenetic therapy and a checkpoint blocker will result in the greatest reduction in tumor weight and increased viability in our mouse model and may have the greatest promise for our patients,” Zahnow said.

In addition to Zahnow, Stone, Chiappinelli and Baylin, other participants included Huili Li, Lauren M. Murphy, Meghan E. Travers, Michael J. Topper, Dimitrios Mathios, Michael Lim, Ie-Ming Shih, Tian-Li Wang Chien-Fu Hung by 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.

The research was supported by grants from the Defense Health Program, through the Department of Defense Ovarian Cancer Research Program, under the Teal Innovator Award OC130454 / W81XWH-14-1-0385; the National Cancer Institute under Awards F32CA183214 and K99CA204592 and Award P30CA006973; Janssen; the Samuel Waxman Cancer Research Foundation Partnership for a Cure Grant; Irving Hansen Fund; and Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.

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