Ovarian cancer is the deadliest of all tumors that affect the female reproductive system because there are few effective treatments available. Now, researchers at the Wistar Institute (USA) have identified a new therapeutic target particularly aggressive claras – carcinoma cells – the form of ovarian cancer, paving the way that could be the first effective targeted therapy for this subtype.
Ovarian cancer is divided into four different subtypes and although is most affected with ovarian cancer initially respond well to standard treatment, the platinum-based chemotherapy, the response rate among people with clear cell subtype is typically low and there is currently no effective therapy for these patients.
One of the challenges in the treatment of ovarian cancer is to find a suitable target to effectively stop the progression of the disease in a personalized manner that is based on the very genetic makeup. And now thanks to this new approach, patients with this particular subtype could have the first effective targeted therapy.
The Wistar team, whose work is published in “Nature Medicine”, began analyzing ARID1A a chromatin remodeler that, when operating normally, enables chromatin, a cell structure that holds together the DNA in our cells, open and allow our cells receive orders. This process determines the behavior of our cells and prevents them from becoming cancerous. However, recent studies have shown that ARID1A is mutated in over 50% of cases of clear cell ovarian carcinoma. In fact, one of the ARID1A has higher mutation rates among all human cancers, but, to date, have not been described therapies designed to address this common mutation.
The researchers were interested in the ratio ARID1A and EZH2, an enzyme that promotes DNA compaction. When this happens, the result is a loss of expression of genes in the compacted areas, thereby preventing transcription of DNA in tumor-fighting protein in our body. Although present in normal cells to maintain a balance in transcription, an overabundance of EZH2 has been associated with the progression of various cancers, including clear cell carcinoma of the ovary.
This led the team to explore the usefulness of EZH2 inhibition as a potential therapeutic tool for treating cancer with mutation in ARID1A. The interaction between ARID1A and EZH2 was confirmed when the researchers observed that ovarian cancers with mutated ARID1A are sensitive to EZH2 inhibition.
The most exciting EZH2 inhibition caused regression of ovarian tumors with mutated ARID1A while had minimal effects on the growth of ovarian tumor with normal or mutated ARID1A in experimental models. Therefore, the answer to EZH2 inhibition correlates with ARID1A mutational status or so-called “synthetic lethality”.
The authors believe that EZH2 inhibitors currently in clinical development may have far-reaching implications. This study provides a much needed ovarian cancer therapeutic strategy clear cell and can be used to help identify patients who could benefit from EZH2 inhibition therapy.
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