Targeted Inhibition of DNA Repair Protein TIRR with Aptamers to Counteract Resistance of Ovarian Cancer Cells to PARP Inhibitors

A new class of molecules, called PARP inhibitors, has shown great promise in treating ovarian cancer. Three PARP inhibitors have already been approved by the Food and Drug Administration (FDA) as drugs against ovarian cancer, while several other PARP inhibitors, sometimes in combination with other drugs, are being tested in clinical trials. PARP inhibitors preferentially kill cancer cells, especially those that are defective in one mechanism of repairing damaged DNA, the so-called homologous recombination or HR repair. Patients whose ovarian cancer cells are defective in HR repair respond best to PARP inhibitor drugs. Unfortunately, over time the cancer cells regain normal HR (i.e., HR is activated), making the patients resistant to PARP inhibitor treatment. Our planned studies address the major clinical problem of PARP inhibitor drug resistance that ovarian cancer patients experience. Our objective is to develop molecules that would inactivate HR in ovarian cancer cells as a means to overcome drug resistance. These molecules would reinstate the killing effect of PARP inhibitors on cancer cells. These molecules would also serve as tools to better understand the mechanisms underlying ovarian cancer. Our group recently contributed in identifying a protein called TIRR that is naturally found in cells and promotes HR repair. We believe that inactivating TIRR in ovarian cancer cells could neutralize the unwanted resistance to PARP inhibitors. We have studied TIRR in great detail and have gained deep knowledge about how it operates. We are now ready to exploit this knowledge to develop molecules that would inactivate TIRR and, as a consequence, inhibit HR in ovarian cancer cells. From our investigations, we know that, to inactivate TIRR, one needs to prevent the physical interaction of TIRR with another protein called 53BP1 that is also found in cells. We opted to screen a very large collection of nucleic acid molecules (these are RNA and DNA molecules called aptamers) to isolate aptamers that would mask the surface of TIRR that contacts 53BP1. Using aptamers to inactivate TIRR is reasonable because TIRR naturally possesses an RNA binding surface that overlaps with its 53BP1 binding surface. Therefore, the chances that we find RNA or DNA aptamers that efficiently block the interaction of TIRR with 53BP1 are high. We will then test in vitro and in cells, including ovarian cancer cells, which aptamers restore the cancer cell killing effect of PARP inhibitors. The short-term impact of our proposed research will be the generation of rigorously tested molecules (aptamers) that enhance the efficiency of PARP inhibitors in killing cancer cells and counteract cell resistance to PARP inhibitors. The long-term impact of our pilot work will be a solid foundation for the development of a new type of drugs with the goal to help eliminate ovarian cancer. As such, our work is relevant to the vision and mission of the Ovarian Cancer Research Program. By way of better understanding and improving the treatment of ovarian cancer, our work in the long term is expected to enhance the health and well-being of Service members, Veterans, retirees, their family members, and all women impacted by this disease.