Combination strategy could hold promise for ovarian cancer

December 5, 2017, Johns Hopkins University School of Medicine
Intermediate magnification micrograph of a low malignant potential (LMP) mucinous ovarian tumour. H&E stain. The micrograph shows: Simple mucinous epithelium (right) and mucinous epithelium that pseudo-stratifies (left - diagnostic of a LMP tumour). Epithelium in a frond-like architecture is seen at the top of image. Credit: Nephron /Wikipedia. CC BY-SA 3.0

Johns Hopkins Kimmel Cancer Center researchers demonstrated that mice with ovarian cancer that 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 that received any of the drugs alone.

The study already spurred a clinical trial in patients. The investigators, led by graduate student Meredith Stone, Ph.D.; postdoctoral fellow Kate Chiappinelli, Ph.D.; and senior author Cynthia Zahnow, Ph.D., believe it could lead to a new way to attack ovarian by strengthening the body's natural against these tumors. It was published in the Dec. 4, 2017, issue of the Proceedings of the National Academy of Sciences.

Ovarian cancer is currently the leading cause of death from gynecological malignancies in the U.S. "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 ," says Zahnow, associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.

Zahnow says that a class of immunotherapy drugs known as checkpoint inhibitors, currently being studied at the Bloomberg~Kimmel Institute for Cancer Immunotherapy, helps the immune system recognize cancers and fight them off. The drugs have shown success in treating melanoma, nonsmall cell lung cancer and renal cell cancers, but they have had only modest effects on ovarian cancer.

Similarly, another class of drugs known as epigenetic therapies has 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 became inspired to investigate a new way to treat ovarian cancer by two recent publications from their group that showed epigenetic drugs turn on immune signaling in ovarian, breast and (Li et al., Oncotarget 2014). These immune genes are activated when epigenetic therapy turns on segments of ancient retroviruses that activate type 1 interferon signaling in the cells (Chiappinelli et al., Cell 2015). Stone, Chiappinelli and Zahnow wanted to know if this increase in immune signaling could lead to the recruitment of tumor killing to the cancer.

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

The researchers started by pretreating the outside of the animal in a culture dish with a DNA methyltransferase inhibitor (a that knocks methyl groups from DNA) called 5-azacytidine (AZA). After injecting these cells into mice, the researchers found that animals receiving 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 . These cells also had increased activity in a variety of genes related to immune response. Pretreating these cells with histone deacetylase inhibitors (HDACis), which 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 was acting on the animals' immune systems. These mice also had decreased ascites, lower tumor burden and longer survival than mice that received just AZA.

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

"We think that AZA and the HDACis are bringing the soldiers, or immune , to the battle. But the checkpoint inhibitor is giving them the weapons to fight," says Zahnow, who also collaborated with epigenetics scientist Stephen Baylin, M.D., on this project.

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

"Combining epigenetic therapy and a checkpoint blocker leads to the greatest reduction in and increase in survival in our mouse model and may hold the greatest promise for our patients," says Zahnow.

Explore further: Two-drug combination may boost immunotherapy responses in lung cancer patients

More information: Meredith L. Stone el al., "Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden," PNAS (2017). www.pnas.org/cgi/doi/10.1073/pnas.1712514114

Related Stories

Two-drug combination may boost immunotherapy responses in lung cancer patients

November 30, 2017
Johns Hopkins Kimmel Cancer Center researchers and colleagues have identified a novel drug combination therapy that could prime nonsmall cell lung cancers to respond better to immunotherapy. These so-called epigenetic therapy ...

Cancer immunotherapy may get a boost by disabling specific T cells

September 7, 2017
Cancer immunotherapy drugs only work for a minority of patients, but a generic drug now used to increase blood flow may be able to improve those odds, a study by Columbia University Medical Center (CUMC) researchers suggests.

Gene circuit switches on inside cancer cells, triggers immune attack

October 19, 2017
Researchers at MIT have developed a synthetic gene circuit that triggers the body's immune system to attack cancers when it detects signs of the disease.

Drug combination may improve impact of immunotherapy in head and neck cancer

September 21, 2017
Checkpoint inhibitor-based immunotherapy has been shown to be very effective in recurrent and metastatic head and neck cancer but only in a minority of patients. University of California San Diego School of Medicine researchers ...

Immune cells help reverse chemotherapy resistance in ovarian cancer

May 20, 2016
Inside each ovarian tumor, there are good cells and bad cells. A new paper explains their roles:

Researchers thwart cancer cells by triggering 'virus alert'

August 27, 2015
Working with human cancer cell lines and mice, researchers at the Johns Hopkins Kimmel Cancer Center and elsewhere have found a way to trigger a type of immune system "virus alert" that may one day boost cancer patients' ...

Recommended for you

Fully reprogrammed virus offers new hope as cancer treatment

May 25, 2018
A cancer treatment that can completely destroy cancer cells without affecting healthy cells could soon be a possibility, thanks to research led by Cardiff University.

Research could help fine-tune cancer treatment

May 25, 2018
Cancer therapies that cut off blood supply to a tumour could be more effective in combination with existing chemotherapeutic drugs—according to new research from the University of East Anglia.

Increasing physical activity linked to better immunity in breast cancer patients, study finds

May 25, 2018
A new study from the University of Toronto's Faculty of Kinesiology & Physical Education has found that moderate to vigorous physical activity may help regulate the levels of C-reactive protein – an important biomarker ...

Low-fat diet tied to better breast cancer survival

May 24, 2018
(HealthDay)—Breast cancer patients who adopted a low-fat diet were more likely to survive for at least a decade after diagnosis, compared to patients who ate fattier fare, new research shows.

A cascade of immune processes offers insights to triple-negative breast cancer

May 24, 2018
Cancer is crafty. To survive and thrive, tumors find a way of thwarting our body's natural systems.

By forming clots in tumors, immune cell aids lung cancer's spread

May 24, 2018
University of North Carolina Lineberger Comprehensive Cancer Center researchers have found that by helping to form clots within tumors, immune cells that flock to a particular type of lung cancer are actually building a foundation ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.