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Therapeutic Targets for Prevention of Cancer-Associated Muscle Loss

Researchers at the University of Nebraska Medical Center have identified a key cell signalling pathway that drives the devastating muscle loss, or cachexia, suffered by many cancer patients.

Cachexia in cancer patients reduce the response to chemotherapy and could result in respiratory or cardiac failure. It is thought to be the direct cause of death among one third of cancer patients.

Professor Pankaj K. Singh from The Eppley Institute for Research in Cancer and Allied Diseases at the University of Nebraska Medical Center, Omaha shared that there are currently no FDA-approved drugs to mitigate cancer-induced cachexia. Highlighting the urgent need to discover effective therapeutic targets against cancer cachexia.

The study was published on 22 May 2020 in the Journal of Experimental Medicine, suggested that targeting a key cell signalling pathway with drug that is in phase 2 clinical trials for diabetes.

Cachexia is most particular affects patients with pancreatic cancer. The research team found that the muscles of pancreatic cancer with cachexia produced reduced level of an enzyme; SIRT1. This was also found in mice with pancreatic cancer, and the researchers found that they could prevent these animals from undergoing cachexia by restoring the levels of this enzyme to normal.

The reduction in SIRT1 in turn produced increased amounts of NOX4 enzyme that generates toxic reactive oxygen species (ROS) capable of inducing muscle degeneration. Treatment of mice models with GKT137831, a drug that inhibits the NOX4 enzyme, showed to prevented muscle loss and extended the life of mice with pancreatic cancer.

NOX4 levels were also elevated in patients undergoing pancreatic cancer­-induced cachexia, suggesting that GKT137831, which is already in phase 2 clinical trials for diabetes and primary biliary cholangitis, could also be used to treat cancer-associated muscle loss.

“Our study establishes the role of the SIRT1-NOX4 axis in mediating cancer cachexia and demonstrate the possibility of targeting this pathway to treat this devastating syndrome,” Singh says. “NOX4 activity is also elevated in muscular dystrophy and other muscle-wasting disorders, suggesting that GKT137831 could be effective in treating muscle loss induced by a variety of pathologies, a possibility that warrants further investigation.” [APBN]