Targeting ARID1A Deficiency in Ovarian Cancer
Abstract
Ovarian clear-cell carcinoma (OCCC) is one of the most aggressive types of cancer. It accounts for approximately 12% of ovarian carcinoma cases. Unlike other types of ovarian carcinoma, OCCC is resistant to DNA-damage-inducing treatments, such as platinum-based chemotherapy (e.g., cisplatin) and radiotherapy. However, these treatments are the mainstays of treatment for OCCC because no effective alternative has been identified. As a result of ineffective treatment, recurrences are more frequent in patients with advanced OCCC than in patients with other types of ovarian carcinoma. The median overall survival time of patients with advanced OCCC (21.3 months) is significantly shorter than that of patients with other types of ovarian carcinoma (40.8 months). Therefore, there is an urgent clinical need to develop new therapeutic strategies to improve patient outcomes. Multiple studies have shown that the ARID1A gene is the most frequently mutated gene in OCCC. ARID1A is mutated in more than 50% of OCCC cases. Our study has two major goals: (1) to determine how mutation of the ARID1A gene causes ovarian cancer and (2) to determine whether we can kill tumor cells with ARID1A mutation but spare normal cells using combination treatments that could be tested soon in clinical trials. If our study is successful, our results will have significant positive impacts for ovarian cancer patients. First, our results may show that ovarian tumors with ARID1A mutations are sensitive to a class of drugs called PARP inhibitors, which are already used to treat patients with other kinds of cancer. This concept can be immediately tested in clinical trials, which could lead to the establishment of PARP inhibitors as an effective, life-prolonging treatment for ovarian cancer patients with mutations of ARID1A. Second, our results may suggest that combining the current standard ovarian cancer therapy (platinum-based chemotherapy and radiation therapy) with therapies that sensitize cells to DNA damage is an effective treatment for ovarian tumors with ARID1A mutations. If so, clinical trials of these combination treatments could be conducted in the near future. In the longer term, our study may lead to personalized treatment for ovarian cancer patients with ARID1A mutations. This personalized treatment would be highly toxic to tumor cells with ARID1A mutation but less toxic to normal cells.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510482
Entities
People
- Guang Peng
Organizations
- United States Army
- University of Texas at Austin