Inhibiting RAD52-Based DNA Repair for Cancer Therapy
Abstract
Most of the time, ovarian cancers have mutations that turn off certain kinds of DNA repair. These tend to be aggressive cancers that kill our mothers, sisters, and female Soldiers. Improvements in therapy would be a wonderful development. This project application describes a focused research approach toward developing personalized treatments for these types of ovarian cancer. DNA damage can come from the normal everyday life of a cell as well as from such things as exposure to chemicals in the environment. Repair of this damage is necessary for a cell, whether normal or cancerous, to continue to function and grow. Cells without DNA repair quickly become disorganized and die or become dormant. In normal cells, there is a system called homologous recombination (HR) that accounts for much of DNA repair. The majority of HR DNA repair is performed by a group of proteins, including BRCA1, BRCA2, and others. There is also a backup set of repair proteins involving RPA and RAD52. In BRCA mutated tumors, the main pathway is disabled so that the cells depend on the backup system to ensure their continued growth. It is said that the cancer is addicted to the backup repair provided by RAD52. In the rest of the person, both systems function. If it were possible to block the backup system, normal cells would not be affected because they would still have the main pathway (normal BRCA system), while cancer cells which had already lost normal BRCA function would no longer have a way to repair much of their DNA damage. This situation is called synthetic lethality and can be exploited to kill cancer cells while leaving normal cells unaffected. Unlike conventional cancer therapies, a personalized chemotherapy system blocking the RPA and RAD52 backup system in HR would likely have much less effect on normal cells, so lessening the negative impact on patient lives. It would instead be targeted at BRCA deficient/mutated cancer cells much more specifically than standard across-the-board treatments. RPA and RAD52 are in physical contact in the cell, and this close association is needed for the work they do. We have found small molecules which inhibit the association of RPA and RAD52 and stops the backup system from working. Three of the eleven small molecules we have found are already approved for use in humans by the FDA. We will determine which of these eleven small molecules works the best in inhibiting RPA and RAD52 and in killing cancer cells but not harming normal cells. Then we will use this information to create even better inhibitors by joining the best ones together. This combination should provide a treatment that more specifically binds the proteins in the backup pathway in the tumor and metastatic sites while being less toxic to the rest of the patient’s body. This would be the best of both worlds with a better targeted treatment and less risk for the patient. If all goes well, we could have improved drugs ready for clinical trials within 5 to 10 years. While these drugs would not end all ovarian cancers, they are expected to retard or even cure the most aggressive cancers that exist in these unlucky patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010816
Entities
People
- Gloria Borgstahl
Organizations
- United States Army
- University of Nebraska Medical Center