New therapeutic approach for difficult-to-treat subtype of ovarian cancer identified

July 24, 2017
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

A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Ovarian clear cell carcinoma accounts for approximately 5 to 10 percent of American cases and about 20 percent of cases in Asia, ranking second as the cause of death from ovarian . People with the clear cell subtype typically do not respond well to platinum-based chemotherapy, leaving limited therapeutic options for these patients.

Previous studies, including those conducted at The Wistar Institute, have revealed the role of ARID1A, a chromatin remodeling protein, in this ovarian cancer subtype. When functioning normally, ARID1A regulates expression of certain genes by altering the structure of chromatin—the complex of DNA and proteins in which DNA is packaged in our cells. This process dictates some of our cells' behaviors and prevents them from becoming cancerous.

"Conventional chemotherapy treatments have proven an ineffective means of treating this group of ovarian cancer patients, meaning that alternative strategies based on a person's genetic makeup must be explored," said Rugang Zhang, Ph.D., professor and co-program leader in Wistar's Gene Expression and Regulation Program and corresponding author of the study. "Therapeutic approaches based on the ARID1A mutation have the potential to revolutionize the way we treat these patients."

Recent studies have shown that ARID1A is mutated in more than 50 percent of cases of ovarian clear cell carcinoma. Mutations of ARID1A and the TP53 are mutually exclusive, meaning that patients with a mutation of ARID1A do not also carry a mutation of TP53. Despite this, the function of TP53, which protects the integrity of our genome and promotes programmed cell death, is clearly impaired as patients with the disease still have a poor prognosis.

In this study, Zhang and colleagues studied the connection between ARID1A and histone deacetylases (HDACs), a group of enzymes involved in key biological functions. They found that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. They were able to show that HDAC6 is typically inhibited by ARID1A, whereas in the presence of mutated ARID1A, HDAC6 levels increase. Because HDAC6 suppresses the activity of TP53, therefore inhibiting its tumor suppressive functions, higher level of HDAC6 allow the tumor to grow and spread.

Using a small molecule drug called rocilinostat that selectively inhibits HDAC6, the Zhang lab found that by blocking the activity of the enzyme in ARID1A-mutated cancers, they were able to increase apoptosis, or programmed cell death, in only those tumor containing the ARID1A mutation. This correlated with a significant reduction in growth, suppression of peritoneal dissemination and extension of survival of animal models carrying ARID1A-mutated ovarian tumors.

"We demonstrated that targeting HDAC6 activity using a selective inhibitor like rocilinostat represents a possible therapeutic strategy for treating ovarian clear cell carcinoma and other tumors impacted by mutated ARID1A," said Shuai Wu, Ph.D., a postdoctoral fellow in the Zhang lab and co-first author of the study. "Inhibitors like the one we used in this study have been well-tolerated in clinical trials, so our findings may have far-reaching applications."

Explore further: New therapeutic strategy discovered for ovarian cancer

More information: ARID1A-mutated ovarian cancers depend on HDAC6 activity, Nature Cell Biology (2017). DOI: 10.1038/ncb3582

Related Stories

New therapeutic strategy discovered for ovarian cancer

February 16, 2015
Ovarian cancer is the deadliest of all cancers affecting the female reproductive system with very few effective treatments available. Prognosis is even worse among patients with certain subtypes of the disease. Now, researchers ...

Study finds gene mutations sensitize tumors to specific cancer drugs

June 11, 2015
Mutations in ARID1a, which are common in many cancer types, disrupt DNA damage repair in cancer cells, allowing the cancer to progress. This gene may also be an Achilles' heel when treating certain tumors, according to a ...

Loss of ARID1A protein drives onset and progress of colon cancer

December 12, 2016
A team of scientists has developed a model system in mice that allows them to look closely at how a protein often mutated in human cancer exerts its tumor-silencing effects. Not all cancers are caused by direct changes in ...

Gene test could pinpoint patients sensitive to new type of cancer drug

December 22, 2016
Testing for a gene commonly mutated in ovarian cancers could pick out patients who will respond well to a promising new class of cancer drugs, a major new study reveals.

Researchers pinpoint two genes that trigger severest form of ovarian cancer

January 27, 2015
In the battle against ovarian cancer, UNC School of Medicine researchers have created the first mouse model of the worst form of the disease and found a potential route to better treatments and much-needed diagnostic screens.

Recommended for you

Scientists develop blood test that spots tumor-derived DNA in people with early-stage cancers

August 16, 2017
In a bid to detect cancers early and in a noninvasive way, scientists at the Johns Hopkins Kimmel Cancer Center report they have developed a test that spots tiny amounts of cancer-specific DNA in blood and have used it to ...

Toxic formaldehyde is produced inside our own cells, scientists discover

August 16, 2017
New research has revealed that some of the toxin formaldehyde in our bodies does not come from our environment - it is a by-product of an essential reaction inside our own cells. This could provide new targets for developing ...

Cell cycle-blocking drugs can shrink tumors by enlisting immune system in attack on cancer

August 16, 2017
In the brief time that drugs known as CDK4/6 inhibitors have been approved for the treatment of metastatic breast cancer, doctors have made a startling observation: in certain patients, the drugs—designed to halt cancer ...

Popular immunotherapy target turns out to have a surprising buddy

August 16, 2017
The majority of current cancer immunotherapies focus on PD-L1. This well studied protein turns out to be controlled by a partner, CMTM6, a previously unexplored molecule that is now suddenly also a potential therapeutic target. ...

Researchers find 'switch' that turns on immune cells' tumor-killing ability

August 16, 2017
Molecular biologists led by Leonid Pobezinsky and his wife and research collaborator Elena Pobezinskaya at the University of Massachusetts Amherst have published results that for the first time show how a microRNA molecule ...

A metabolic treatment for pancreatic cancer?

August 15, 2017
Pancreatic cancer is now the third leading cause of cancer mortality. Its incidence is increasing in parallel with the population increase in obesity, and its five-year survival rate still hovers at just 8 to 9 percent. Research ...

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.