The National Cancer Institute has awarded a team led by UNC Lineberger’s Dale Ramsden, PhD, professor in the UNC School of Medicine Department of Biochemistry and Biophysics, a five-year, $8.8 million program project grant to study an enzyme called DNA polymerase theta. This enzyme is part of an important pathway that repairs damage to genomes, with particular significance in some cancers.
The research is a nationwide collaborative effort. It brings together experts in molecular biology (Ramsden) and cancer cell biology (Gaorav Gupta, MD, PhD, assistant professor in the UNC School of Medicine Department of Radiation Oncology and UNC Lineberger member), biochemistry (Richard Wood, PhD, MD Anderson Cancer Center, Houston), structural biology and mechanism (Sylvie Doublié, PhD, University of Vermont, Burlington) and biophysics (Eli Rothenberg, PhD, Perlmutter Cancer Center, New York).
The team’s experiments will focus on the mammalian form of DNA polymerase theta, or POLQ. The enzyme is known to be essential for the development of many hereditary breast cancers, particularly those defined by mutations in BRCA1/2 genes. There are currently several effective therapies for patients with breast or ovarian cancers that have mutations in either or both BRCA1 and BRCA2 genes. These therapies principally include PARP inhibitors that work by keeping cancer cells from repairing themselves, and thus inducing cancer cell death. But PARP inhibitors are often given in combination with conventional chemotherapy drugs and have some consequential side effects.
Scientists are always on the lookout for new and better approaches to fighting cancer, which is where developing a targeted POLQ inhibitor is of interest. To date, there has been little known, both in normal cells and cancer cells, about the structure, mechanism of action, and the biological role of this enzyme. The lack of basic biological knowledge of how POLQ works led to the awarding of this grant.
The team’s research efforts will start in the lab by looking at POLQ at the cellular level. They have already developed a unique method that can assess, with a high degree of accuracy, the activity of the POLQ enzyme and its repair pathway in cells. Eventually, the investigators intend to study the enzyme’s role in mouse models before undertaking the ultimate task of figuring out how possible POLQ-related therapies could benefit patients.
The scientists have postulated POLQ would be an advantageous target because it becomes essential only in combination with certain tumor-specific contexts. Most intriguingly, the researchers already have data that shows that potential therapies directed at POLQ could improve the effectiveness of PARP inhibitors for the treatment of certain types of breast cancer.
Because of the depth of expertise involved, the team will cast a wide net in their work. The researchers originally thought that hereditary, BRCA1/2-deficient breast and ovarian cancers would be the primary targets of a POLQ therapy. But even though their work is just beginning, they believe that up to 30% of all breast cancers (not just those that are BRCA1/2 deficient), and perhaps other cancers could benefit from treatment with a POLQ-based therapy.