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 at The Wistar Institute have identified a new therapeutic target in 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.
The findings were published online by the journal Nature Medicine.
Ovarian cancer is divided into four different histological subtypes. One of the subtypes is ovarian clear cell carcinoma, which affects approximately 5 to 10 percent of American ovarian cancer patients and about 20 percent of patients in Asia. While 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 Rugang Zhang, Ph.D., associate professor in Wistar’s Gene Expression and Regulation Program and corresponding author of the study.
“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 percent 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.
Ovarian cancer is any cancerous growth that may occur in different parts of the ovary. The majority of ovarian cancers arise from the epithelium (outer lining) of the ovary. According to the American Cancer Society it is the 8th most common cancer among women in the USA (excluding non-melanoma skin cancers). In the UK ovarian cancer is the fifth most common cancer among females, after breast cancer, bowel cancer, lung cancer and uterine cancer (cancer of the uterus).
Approximately 5,500 women in the UK and 21,000 women in the USA are diagnosed with ovarian cancer each year. Worldwide, around 140,000 women die of ovarian cancer every year.
Tragically, the overall five year survival rate is only 46 per cent in most developed countries (it is lower for more advanced stages). However, according to the National Cancer Institute, if diagnosis is made early, before the tumor has spread, the five year survival rate is nearer 93 per cent. In 2009 scientists in the US said that current tests for diagnosing ovarian cancer are not good enough .
Even modern screening tests for ovarian cancer, which include a blood test for the CA 125 marker, combined with ultrasound, often result in unnecessary surgery and “..are failing to catch early signs of the disease..”, a study at the University of Alabama at Birmingham Comprehensive Cancer Center revealed.
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.”
The term “ovarian cancer” includes several different types of cancer that all arise from cells of the ovary. Most commonly, tumors arise from the epithelium, or lining cells, of the ovary. These include epithelial ovarian (from the cells on the surface of the ovary), fallopian tube, and primary peritoneal (the lining inside the abdomen that coats many abdominal structures) cancer. These are all considered to be one disease process. There is also an entity called borderline ovarian tumors that have the microscopic appearance of a cancer, but tend not to spread much.
However, there are also less common forms of ovarian cancer that come from within the ovary itself, including germ cell tumors and sex cord-stromal tumors. All of these diseases will be discussed, as well as their treatment.
Epithelial ovarian cancer
Epithelial ovarian cancer (EOC) accounts for a majority of all ovarian cancers. It is generally thought of as one of three types of cancer that include ovarian, fallopian tube, and primary peritoneal cancer that all behave, and are treated the same way, depending on the type of cell that causes the cancer. The four most common cell types of epithelial ovarian cancer are serous, mucinous, clear cell, and endometrioid. These cancers arise due to DNA changes in cells that lead to the development of cancer. Serous cell type is the most common variety. It is now thought that many of these cancers actually come from the lining in the fallopian tube, and fewer of them from the cells on the surface of the ovary, or the peritoneum. However, it is often hard to identify the sources of these cancers when they present at advanced stages, which is very common.
“With EZH2 inhibitors currently in clinical development, we believe that our findings will have far-reaching implications,” said Benjamin Bitler, Ph.D., a member of the Zhang laboratory, an American Cancer Society postdoctoral fellowship recipient, and first author of the study. “Excitingly, this study provides a much-needed therapeutic strategy for clear cell ovarian cancer and can be utilized to aid in the identification of patients that could benefit from EZH2 inhibition therapy.”
“This study highlights the impact of how team science in our Cancer Center can bring about transformative discoveries,” said Dario C. Altieri, M.D., director of The Wistar Institute Cancer Center and executive vice president and chief scientific officer of The Wistar Institute. “This has been our approach to better understand difficult-to-treat and recalcitrant tumors, like ovarian cancer, and we are thrilled that this groundbreaking research tangibly advances the prospects of better, more targeted therapies for these patients.”
This work was supported by the National Institutes of Health grants R01CA160331 and R01CA16337, the U.S. Department of Defense Ovarian Cancer Academy Award OC093420 and the Ovarian Cancer Research Fund Program Project Development Grant. Other grants supporting this project include the American Cancer Society postdoctoral fellowship PF-13-058-01-TBA and the National Institutes of Health training grant T32CA9171-35. Core facilities support was provided by the Cancer Center Support Grant (CCSG) CA010815.
Other co-authors of this study from The Wistar Institute include Katherine M. Aird, Azat Garipov, Hua Li, Michael Amatangelo, Andrew V. Kossenkov, David C. Schultz, Qin Liu, José R. Conejo-Garcia, and David Speicher. Co-authors from other institutions included Ie-Ming Shih from Johns Hopkins Medical Institutions.
The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has long held the prestigious Cancer Center designation from the National Cancer Institute. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. Wistar Science Saves Lives.
The Wistar Institute