The STING Paradox in Serous Ovarian Cancers
Abstract
Ovarian cancer is split into different subtypes, each with their own clinical features and outcomes. One of the rarer forms of ovarian cancer is called low-grade serous ovarian cancer, which accounts for about 5% of ovarian cancer cases. Compared to other subtypes of ovarian cancer, low-grade serous ovarian cancer tends to occur in younger, often pre-menopausal women. While this tumor grows more slowly than some of the other types of ovarian cancer, it is stubbornly resistant to almost all therapeutics. The first line chemotherapy to treat this cancer is a combination of platinum and taxanes, but only 5% of patients will respond. As a result, outcomes for patients with low-grade serous ovarian cancer are very poor, with only 10-20% of patients living more than 10 years. There is an urgent need for creative new treatment strategies for these patients. For tumors to grow, they need to disguise themselves from the immune system. A molecule within cells called STING is responsible for recognizing viral DNA inside of cells and starting the process for signaling the immune system. When tumors are forming, they sometimes generate broken pieces of DNA that are recognized by STING. Therefore, these tumors must inhibit STING activity in order to grow. In looking at STING levels in various ovarian tumors, we were surprised to find that STING is expressed at very high levels in low-grade serous ovarian cancers and their precursor lesions. Strangely, other proteins in the STING pathway are not present in high levels, suggesting that the pathway is unable to function properly. Our research idea is to exploit the high levels of STING as a therapeutic target. In the first part of the study, we will test the levels of proteins in the STING pathway of low-grade serous ovarian tumors, their precursor lesions, and other types of ovarian cancers. This will allow us to determine at which point the pathway is broken. We will find out whether we are able to put these proteins back into low-grade serous ovarian cancer cells to reconstitute STING signaling. If we are able to reconstitute the STING pathway, it would be a way that we could get the immune system to recognize low-grade serous tumors. As low-grade serous ovarian cancers appear to be defective in their viral sensing system, in the second part of these studies, we will determine whether these tumors are sensitive to oncolytic viral therapy. Oncolytic viruses are specially constructed so that they are only lethal to tumor cells, while having no adverse effects on normal cells. Oftentimes when cancer cells become resistant to oncolytic viruses, it is because of the STING pathway. We think that because low-grade serous ovarian cancers lack functional STING pathway, they will be susceptible to oncolytic viruses. One of the oncolytic viruses we will test has been specially designed to kill tumor cells, as well as activate the immune system to further enhance tumor clearance. These studies have the potential for having an impact on improving outcomes for low-grade serous ovarian cancer patients. If these studies are successful, we will have the rationale for further preclinical studies in the hopes of working towards a clinical trial for the use of oncolytic viruses for the treatment of low-grade serous ovarian cancers. These studies align with the mission and vision of the Ovarian Cancer Research Program, as they are designed to test new therapeutic strategies and will lay the groundwork for future clinical trials. This could result in improving outcomes for all women impacted by this disease, including Service Members, Veterans, retirees, and their family members, with an ultimate goal of eliminating ovarian cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110785
Entities
People
- Dawn Cochrane
Organizations
- Provincial Health Services Authority
- United States Army