A researcher at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center received a five-year, $2.5 million grant from the National Cancer Institute to develop a novel therapy to treat lung cancer.
The research led by John Turchi, PhD, uses a small drug-like molecule designed to disrupt the DNA repair pathways that allow lung cancer cells to continue replicating and tumors to grow. Turchi is the Tom and Julie Wood Family Foundation Professor of Lung Cancer Research at Indiana University School of Medicine.
The body repairs DNA damage daily from things such as UV rays from the sun, toxins in the air, and chemicals from cigarettes. Turchi researches a protein called replication protein A (RPA), which binds to single-strand DNA to signal DNA damage response (DDR) to repair the damage and make new cells.
“The novel therapeutics we are developing would treat patients who often have limited therapeutic options, which include smoking-induced lung cancers,” Turchi said. “We think this group of patients could benefit from what we’ve learned over the last 30 years from our understanding of this pathway.”
Lung cancer is the leading cause of cancer death in men and women and accounts for more than 20 percent of all cancer deaths. Cancer cells divide more rapidly than normal cells, putting them under replication stress. The cancer cells rely on the DNA damage response to ensure they can continue to divide and thrive. And that’s what Turchi wants to exploit to stop cancer.
“When we can inhibit replication protein A from binding to single-stranded DNA during this replication stress, we can induce massive cell death—and that’s specific to cancer, which gives us our therapeutic window,” Turchi said.
The RPA inhibitor developed by IU researchers targets cancer through a different mechanism from other cancer therapies. RPA binds to damaged DNA like a flashing light to signal it needs to be repaired. The RPA inhibitor stops that signal, so the cells die.
In addition to applications for lung cancer, Turchi’s research team is exploring the RPA inhibitor to treat ovarian cancer. Lung and ovarian cancers are both marked by many mutations in the DNA damage response pathway.
Turchi’s lab is now working to move findings from the cancer research lab to patients in the clinic based on decades of research into these pathways.
“We are now to the point where our work is less of the discovery and more of the implementation and translational work that is driven by clinical possibilities,” Turchi said.
For this research, Turchi established new collaborations with cancer center researchers at core research facilities: Jun Wan, PhD, director of Cancer Bioinformatics Core; Karen Pollok, PhD, director of In Vivo Therapeutics Core; and Andi Masters, lab director of Clinical Pharmacology Analytical Core. Cancer center physician-scientists Shadia Jalal, MD, and Catherine Sears, MD, are providing vital clinical perspectives as the research team moves toward clinical applications.
“The complementary expertise of the many cancer center researchers is going to allow us to answer some really important questions and ultimately impact patients’ lives,” he said.
