Researchers have identified a new therapeutic target for a particularly aggressive form of ovarian cancer, paving the way for what could be the first effective targeted therapy of its kind for the disease. Their findings were published in Nature Medicine (2015; doi:10.1038/nm.3799).
Ovarian cancer is the deadliest of all cancers affecting the female reproductive system, and very few effective treatments are available. Prognosis is even worse among patients with certain subtypes of the disease.
Ovarian cancer is divided into four different histological subtypes. One of the subtypes is ovarian clear cell carcinoma, which affects approximately 5% to 10% of American women with ovarian cancer and approximately 20% of patients in Asia. Although most patients with ovarian cancer initially respond well to standard-care platinum-based chemotherapy, the response rate among those with the clear cell subtype is typically low and there is currently no effective therapy for these patients. This underscores the need for a new approach to treating this deadly disease.
“One of the significant challenges with the treatment of ovarian cancer is finding a suitable target that effectively halts the progression of the disease in a personalized manner based on one’s genetic makeup,” said corresponding author Rugang Zhang, PhD, associate professor at The Wistar Institute’s Gene Expression and Regulation Program in Philadelphia, Pennsylvania.
“With this study, we have done just that. For patients with this particular subtype, this newly discovered targeted approach may eventually lead to the first effective targeted therapy they’ve ever had.”
The team at Wistar began by looking at ARID1A, a chromatin remodeler. When functioning normally, ARID1A makes it possible for chromatin, a cellular structure that holds DNA together in our cells, to open up and allow our cells to receive commands. This process dictates our cells’ behavior and prevents them from becoming cancerous.
However, recent studies have shown that ARID1A is mutated in more than 50% of cases of ovarian clear cell carcinoma. In fact, ARID1A has one of the highest mutation rates among all types of human cancer. To date, though, no therapies designed to target this common mutation have been described.
What interested the researchers was the relationship between ARID1A and EZH2, an enzyme that promotes compaction of the DNA. When this happens, the result is a loss of expression of genes in the compacted regions, thus preventing the transcription of DNA into tumor-fighting proteins for our body. While present in normal cells to maintain a transcriptional balance, an overabundance of EZH2 has been associated with the progression of different types of cancer, including ovarian clear cell carcinoma.
This prompted the team to explore the utility of EZH2 inhibition as a potential therapeutic means of treating cancer with ARID1A mutation. The interplay between ARID1A and EZH2 was confirmed when the researchers observed that ARID1A-mutated ovarian cancers are sensitive to EZH2 inhibition.
Most exciting of all, EZH2 inhibition caused the regression of ovarian tumors with mutated ARID1A, while having minimal effects on the growth of ovarian tumor with normal or unmutated ARID1A in experimental models. Thus, the response to EZH2 inhibition correlates with ARID1A mutational status or the so-called “synthetic lethality.” Further, EZH2 inhibitors are currently in clinical development.