VCU Massey Cancer Center researcher Senthil Radhakrishnan, Ph.D., member of Massey’s Cancer Molecular Genetics research program and assistant professor of pathology at the VCU School of Medicine, was awarded a $1.6 million R01 grant from the National Institute of General Medical Sciences to study the genetic properties that facilitate cellular stress response to proteasome inhibition as a means to inform the development of more effective cancer therapies.

Proteasome is an essential cellular structure that destroys proteins when they are no longer needed. Proteasome inhibitors are drugs that obstruct the function of proteasome, and the only FDA-approved proteasome inhibitors currently available are approved for the treatment of multiple myeloma (cancer of the plasma cells) and mantle cell lymphoma (a subtype of non-Hodgkin lymphoma that occurs in white blood cells).

“When proteasome is inhibited by these drugs, the cells cannot degrade proteins anymore and there are a lot of proteins that accumulate,” Radhakrishnan said. “That puts a lot of stress on the cells. Normal cells can cope with it, but many cancer cells cannot. Multiple myeloma and mantle cell lymphoma are very sensitive to this type of stress and that’s why those tumors are susceptible to proteasome inhibitors.”

Previous research conducted by Radhakrishnan identified a transcription factor — a genetic information pathway that helps convert DNA into RNA — called NRF-1 that gets activated to help make more proteasome when it is inhibited. Cancer cells are thought to be hyper-dependent on proteasome because a number of proteins have to be destroyed in a timely manner to support the rapid cell division of cancer cells.

“If we find a way to block the NRF-1 pathway, then maybe we can make proteasome inhibitors more effective,” Radhakrishnan said.

Through a five-year grant, Radhakrishnan will work to further understand the biological mechanisms of NRF-1 in an effort to improve current treatments for multiple myeloma and mantle cell lymphoma, as well as potentially expand the use of proteasome inhibitors to treat other forms of disease, including triple negative breast cancer and Ewing’s sarcoma, a cancer of the bones.

Beyond cancer, Radhakrishnan said that a better understanding of the NRF-1 pathway could also inform more effective treatments for neurodegenerative diseases in which proteasome is known to be less functional. 

“If we can find a way to activate this pathway and make more proteasome, maybe it will be beneficial in neurodegenerative diseases as well,” Radhakrishnan said.

Radhakrishnan emphasized that regardless of whether the end goal is to inhibit the function of the NRF-1 pathway to enhance the efficacy of cancer drugs or to augment the pathway to treat other types of disease, the first step is to completely understand how NRF-1 operates.

He is collaborating on this study with David Gewirtz, Ph.D., member of the Developmental Therapeutics research program at Massey and a professor in the Department of Pharmacology and Toxicology at the VCU School of Medicine, and Joseph Landry, Ph.D., member of the Cancer Molecular Genetics research program at Massey and assistant professor in the Department of Human and Molecular Genetics at the VCU School of Medicine.