- Chromatin remodelers and ARID1A are emerging as a novel class of genes, which are linked to various types of cancers
- ARID1A-mutated ovarian cancers depend on HDAC6 activity
- Rocilinostat inhibitor treats ovarian clear cell carcinoma and other tumors impacted by mutated ARID1A
A new therapeutic strategy has been discovered for one form of ovarian cancer that is difficult-to-treat, reveals a new study. The findings of the study were published in Nature Cell Biology
by Wistar scientists.
Approximately, 5 to 10 percent of ovarian cancer cases in the U.S. and about 20 percent of cases in Asia occur due to ovarian clear cell carcinoma that ranks second leading cause of death from ovarian cancer.
‘Pharmacological inhibition of HDAC6 is a new therapeutic strategy for ARID1A-mutated cancers like the ovarian clear cell carcinoma.’
There are limited therapeutic options for these patients with clear cell subtype, as they do not respond well to platinum-based chemotherapy.
Role of Chromatin Remodeling Protein
The role of ARID1A, a chromatin remodeling protein, in this ovarian cancer subtype has been revealed in the previous studies conducted at The Wistar Institute.
ARID1A regulates expression of certain genes when functioning normally. It alters the structure of chromatin (the complex of DNA) and proteins in which DNA is packaged in the cells. This process dictates the behavior of the cell; thereby, preventing the cells from becoming cancerous.
Rugang Zhang, Ph.D, professor and co-program leader in Wistar's Gene Expression and Regulation Program and corresponding author of the study said: "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."
He also said that the therapeutic approaches which were based on the ARID1A mutation were found to have the potential to revolutionize the way these patients are treated.
ARID1A was found to be mutated in more than 50 percent of cases of ovarian clear cell carcinoma, reveal recent studies.
The tumor suppressor gene TP53 and mutations of ARID1A are mutually exclusive. This means that patients with a mutation of ARID1A do not necessarily have to carry a mutation of TP53. Despite this, the function of TP53 is clearly impaired, as patients show signs of poor prognosis. The function of TP53 is to protect the integrity of the genome and promote programmed cell death.
The connection between ARID1A and histone deacetylases (HDACs) have been studied by Zhang and his colleagues in this study.
HDACs are a group of enzymes involved in key biological functions and the HDAC6 activity is very important in ARID1A-mutated ovarian cancers.
The research team was able to show that the HDAC6 has been inhibited by ARID1A. But the levels of HDAC6 increase in the presence of mutated ARID1A., as HDAC6 suppresses the activity of TP53.
Inhibiting the tumor suppressive functions increases the levels of HDAC6 and allows the tumor to grow and spread.
Role of Rocilinostat Inhibitor
Zhang lab found that using rocilinostat, a small molecule drug which selectively inhibits HDAC6 blocks the activity of the enzyme in ARID1A-mutated cancers.
The research team was able to increase programmed cell death in only those tumor cells that contained the ARID1A mutation. By suppressing peritoneal dissemination and extending the survival rate of the animal models carrying ARID1A-mutated ovarian tumors was found to significantly reduce in tumor growth.
Shuai Wu, Ph.D., a postdoctoral fellow in the Zhang lab and co-first author of the study said: "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."
The inhibitors that have been used in the study were found to be well-tolerated in the clinical trials and the findings may have far-reaching applications, said Wu.
Ovarian cancer is one of the most common types of cancer in women and is responsible for 5% of the total cancer deaths among women.
Ovarian cancer affects both the ovaries and is referred to as the 'silent killer' as the symptoms go unnoticed in the early stages until the disease advances.
Treatment of ovarian cancer depends on a number of factors, including the stage of the disease and the general health of the patient.
- Shuai Wu, et al. ARID1A-mutated ovarian cancers depend on HDAC6 activity. Nature Cell Biology (2017). DOI: 10.1038/ncb3582