Ovarian clear cell carcinoma is one of the most difficult forms of ovarian cancers to treat, but there may be a new approach for therapy. The potential new form of therapy was discovered by Wistar scientists and discussed in detail in the online medical journal, Nature Cell Biology.
Between 5 and 10 percent of the ovarian cancer cases in the United States and about 20 percent of the ovarian cancer cases in Asia are ovarian clear cell carcinoma cases. Clear cell carcinoma ranks as the second leading cause of death in women from ovarian cancer. Women who are diagnosed with the clear cell subtype often face a limited set of therapeutic options because they generally do not respond well the platinum-based chemotherapy.
The Wistar Institute has conducted a number of studies that show the role of the chromatin remodeling protein, ARID1A, in clear cell carcinoma. In a healthy body that is functioning at normal capacity, the expression of certain genes is regulated by ARID1A. ARID1A regulates those genes by altering the structure of chromatin. Chromatin is the complex of proteins and DNA and in which DNA is packaged in the body's cells. This process prevents some of the body's cells from becoming cancerous by dictating the behaviors of the cells.
Rugang Zhang, Ph.D. is a professor, the co-program leader in Wistar's Gene Expression and Regulation Program, and the corresponding author of this study. According to Zhang, conventional and previous forms of chemotherapy treatments have shown themselves to not be an effective method for treating this particular subtype of ovarian cancer patients. Therefore, alternative therapeutic approaches, particularly one based on a patient's genetic makeup, should be explored as soon as possible. Zhang goes on to state that by exploring the strategy of using the ARID1A mutation as a novel therapeutic approach, a revolution could be made in the way these patients are treated.
The ARID1A mutation occurs in more than 50 percent of ovarian clear cell carcinoma cases, according to some recent studies. Another type of mutation that can occur is called TP53. The function of TP53 is to suppress tumors by protecting the integrity of the human genome and through the promotion of programmed cell death. The function of TP53 is severely impaired in patients with ovarian cancer, leaving a poor prognosis. Despite the similarities between the ARID1A mutation and the TP53 mutation, the two are not necessarily concurrent. A person can have one mutation without having the other.
In this particular research study, Zhang and several colleagues explored the link between ARID1A and histone deacetylases (HDACs). HDACs are a group of enzymes that are instrumental in several key biological functions. The researchers discovered that elevated activity levels of HDAC6 is present in ovarian cancer cases with the ARID1A mutation. Under normal circumstances, ARID1A would inhibit the activity level of HDAC6. However, when ARID1A was mutated, the activity levels of HDAC6 actually increased. As previously mentioned, HDAC6 inhibits the activity levels of TP53, which decreases its ability to suppress tumors. As a result of this link, increased levels of HDAC6 could allow tumors to grow and spread to other areas within the body.
The small molecule drug, rocilinostat, selectively inhibits HDAC6. The Zhang lab used rocilinostat to discover that when they blocked the activity levels of the enzyme in the mutated ARID1A cancers, the were able to promote programmed cell death (apoptosis). The team was able to isolate the cell death to only the tumor cells that contained the ARID1A mutation. As a result of this targeted cell death, the team was able to dramatically suppress peritoneal dissemination, significantly reduce the growth of tumors, and extend the survival of the animal models that carried the ovarian tumors with the ARID1A mutation.
New Imaging Test Can Show Key Enzyme in Ovarian Cancer to Help Guide Treatment Choices
A team of researchers from the Perelman School of Medicine at the University of Pennsylvania have discovered a new imaging test that might give doctors the chance to uncover ovarian cancer patients who are candidates for a new form of treatment that targets a key enzyme necessary for cancer cells to survive. As of this publication, patients who have epithelial ovarian cancer and the BRCA1 mutations are considered to be prime candidates for the treatment. However, there are no current ways to evaluate the levels of enzymes to help guide doctors and patients to choices for therapeutic treatment. A new type of imaging test that will be presented at the upcoming 2017 American Association for Cancer Research Annual Meeting in Washington, D.C., may help doctors and researchers in identifying patients that could be candidates for the specialized new treatment that blocks the enzyme and may include patients who do not have the BRCA mutation, as well.
The researchers were able to use the imagine in order to detect Poly (ADP-ribose) Polymerase 1 (PARP-1) and discovered drugs that block the enzyme have as much or more impact on treatment than the restoration of the BRCA1 mutation. PARP-1 is an enzyme that functions to help cancer cells survive by repairing their DNA. PARP-1 has already long been a target of several different breast and ovarian cancer therapies. Doctors are able to trap the enzyme on cancer DNA by using a PARP inhibitor. By trapping the enzyme, doctors can cause the cancer cells to die. This new research by the team at the University of Pennsylvania may be a huge asset at helping doctors to find those patients who would benefit the most from the therapy with PARP inhibitors.
According to the study's lead author, Mehran Makvandi, PharmD, RPh, ANP, and instructor at Radiology at Penn, research already exists to support the idea that PARP inhibitors could be a very effective tool in the treatment of cancer with the BRCA1 gene mutation. Marvandi says that the team wants to have their radiotracer technology validated as a quantitative biomarker for PARP-1. The goal of the study is to be able to select ovarian cancer patients who can benefit from the PARP inhibitor therapy.
As part of the study, the researchers used two different types of ovarian cancers. One of the ovarian cancers had the BRCA1 mutation and the other did not. The team used special genetic editing to remove the PARP-1 from the BRCA1 mutated cancer cells. Next, the team exposed the remaining cells to the PARP inhibitors. The researchers also exposed the cells to cisplatin, which is a chemotherapy drug. The team the repeated the same experiment with the other types of cancer cells, but left the PARP-1 intact and then compared the results.
Makvandi and colleagues carefully evaluated the difference between losing PARP-1 and gaining BRCA1. The team found that in a lot of the PARP inhibitors, the loss of PARP-1 led to equal amounts of or more resistant to the therapy as did the restoration of the BRCA1 function. The team also discovered that the new radiotracer method helped to reflect the sensitivity to PARP inhibitors by measuring the expressed PARP-1.
New imaging test can show key enzyme in ovarian cancer to help guide treatment choices (2017, April 3). [Web]. New-Medical. Retrieved from: https://www.news-medical.net/news/20170403/New-imaging-test-can-show-key-enzyme-in-ovarian-cancer-to-help-guide-treatment-choices.aspx
Wistar scientists discover new therapeutic strategy for difficult-to-treat form of ovarian cancer (2017, July 24). [Web]. In News Medical. Retrieved from: https://www.news-medical.net/news/20170724/Wistar-scientists-discover-new-therapeutic-strategy-for-difficult-to-treat-form-of-ovarian-cancer.aspx