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VCU Massey Cancer Center scientist Senthil Radhakrishnan, Ph.D., has been awarded $792,000 over four years by the American Cancer Society to explore a new approach to treating triple-negative breast cancer (TNBC).

TNBC accounts for about 15 percent of all breast cancers diagnosed and disproportionately impacts Black women. It’s an aggressive disease that cannot be treated with hormone therapy, leaving chemotherapy as one of the only options after surgery. Radhakrishnan’s work explores using a class of drugs called proteasome inhibitors.

“Proteasome inhibitors block cells’ ability to break down proteins to the point they accumulate and kill the cell,” says Radhakrishnan, a member of Massey’s Cancer Molecular Genetics research program and associate professor of pathology at the VCU School of Medicine. “We’re testing whether we can increase the effectiveness of this class of drugs to create new treatment options for TNBC as well as other cancers.”

Radhakrishnan and his team have previously shown that cancer cells can overcome the effect of proteasome inhibitors through processes controlled by a protein known as NRF-1. NRF-1 is a transcription factor that controls the rate at which proteasomes are encoded from genetic information. By blocking NRF-1, the team believes they can make proteasome inhibitors more effective against a range of cancers.

"Our preliminary results indicate that blocking the NRF-1 pathway greatly increases the action of the proteasome inhibitor carfilzomib in TNBC cells,” said Radhakrishnan. “This funding will help us carry out complex experiments needed to obtain preclinical proof, which could prompt translation of our findings from the lab to the clinic.”

Over the next four years, Radhakrishnan and his collaborators will develop mouse models harboring TNBC tumors. They will test whether combining carfilzomib with NRF-1 inhibition prolongs survival and reduces tumor burden compared to carfilzomib alone.

“If successful, our work could lead to the development of new drug combinations that improve survival for many patients and also provide motivation for testing this combination in other cancer types,” said Radhakrishnan.

Co-investigators on this research include David Gewirtz, Ph.D., member of the Developmental Therapeutics research program at Massey and a professor in the Department of Pharmacology and Toxicology at VCU School of Medicine; Jennifer Koblinski, Ph.D., member of the Cancer Biology research program at Massey and assistant professor in the Department of Pathology at VCU School of Medicine; Chuck Harrell, Ph.D., member of the Cancer Biology research program at Massey and associate professor in the Department of Pathology at VCU School of Medicine; and Joseph L. McClay, Ph.D., associate professor in the Department of Pharmacotherapy & Outcomes Science at VCU School of Pharmacy.

Written by: John Wallace