Vulnerability of ARID1A-Deficient Ovarian Cancer to Pyrimidine Synthesis Blockade
Abstract
The expression of the protein ARID1A is often lost in ovarian cancer due to a mutation that arises during cancer development. Apart from previously known functions of ARID1A in fine-tuning gene expression, our laboratory recently discovered that ARID1A is involved in the regulation of an enzyme called CAD. The CAD enzyme catalyzes important steps in the pyrimidine biosynthesis pathway, which is used by cancer cells to make building blocks of DNA and RNA needed for tumor growth and spread. Based on our discovery, we hypothesized that cancer cells that have lost ARID1A expression would show changes in CAD and pyrimidine biosynthesis that could be targeted in cancer therapy. Supporting this hypothesis, our data show that ARID1A-deficient ovarian cancer cells have increased activity and dependency on pyrimidine biosynthesis and that blocking this pathway may be an effective new way to treat these cancers. Additional new data show that ARID1A-deficient ovarian cancer cells may be exquisitely sensitive to dihydroorotate dehydrogenase inhibitors, which block the next step in pyrimidine biosynthesis after CAD. Two of these inhibitors are Food and Drug Administration (FDA)-approved for the treatment of autoimmune disease and have been safely used by these patients for many years. A central problem in ovarian cancer is that all ovarian cancers are treated similarly with cytotoxic chemotherapy despite underlying genetic differences that affect the response to treatment. ARID1A mutations are associated with resistance to standard chemotherapy used for ovarian cancer. Therefore, these patients may be exposed to great toxicity with little benefit when treated with standard chemotherapy. We have identified a promising new targeted treatment strategy based on recent discoveries in our laboratory. In the proposed research, we will conduct experiments that will develop this new treatment strategy for translation to the clinic. Since the targeted compounds to be tested in the proposed experiments are already FDA-approved for other clinical uses, the optimal treatment strategies identified in our research could be quickly implemented in the clinic to help patients with ovarian cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610196
Entities
People
- Gloria Huang
Organizations
- Albert Einstein College of Medicine
- United States Army