A research team at KAIST announced on Aug. 2 the development of an RNA-based therapeutic strategy designed to block a brain signal responsible for cancer-associated cachexia, a complication that causes severe muscle loss in cancer patients.
The joint effort, led by Professor Minho Shong and Professor Jinkuk Kim from the Graduate School of Medical Science and Engineering, along with THOR Therapeutics CEO Minho Shong, identified a new approach to treat cancer cachexia. Cancer cachexia affects between 50 and 80 percent of all cancer patients. As metabolism is disrupted by cancer cells, patients lose weight and muscle mass despite adequate nutrition, leading to physical decline. Existing treatments have primarily focused on temporarily increasing appetite without addressing underlying metabolic dysfunction.
The researchers targeted the GDF15-GFRAL pathway in the brainstem. GDF15 is secreted in large amounts as cancer progresses and binds to its receptor GFRAL in the brainstem, sending signals that cause the body to stop eating and break down muscle and fat stores. The team developed an antisense oligonucleotide (ASO) therapy—an RNA-based gene therapy—to suppress production of GFRAL at the genetic level.
By blocking GFRAL production during the RNA stage, this approach interrupts the cachexia-inducing signal at its source. In mouse models with advanced cachexia, treatment resulted in reduced muscle and fat loss as well as restored metabolic function. Survival rates were notably higher among treated mice: 90 percent survived until day 50, compared with only 20 percent in untreated controls.
Professor Shong said, "While existing therapies have only temporarily boosted appetite, this study is significant in that it directly targeted a key receptor in the brainstem at the RNA level to suppress the root cause of cancer cachexia." He also said that further preclinical research will be conducted alongside drug manufacturing efforts and quality-control systems before clinical development begins for patients by 2030.
Dr. Hyunjung Hong from KAIST's Graduate School of Medical Science and Engineering; Dr. Minhee Lee from THOR Therapeutics; and Dr. Minsung Park from KAIST participated as co-first authors on this work published July 27 in Cell Reports Medicine.
