Blocking a Brain Signal To Counter Cancer-Associated Cachexia

A new path has opened toward stopping cancer-associated cachexia, a devastating complication that gradually wastes patients away. A KAIST research team has developed an RNA-based therapeutic strategy that blocks a brain signal to prevent muscle loss and extend survival.

KAIST (President Choongsik Bae) announced on the 2nd of August that a joint research team led by Professor Minho Shong and Professor Jinkuk Kim from the Graduate School of Medical Science and Engineering, together with the KAIST faculty startup THOR Therapeutics (CEO Minho Shong), identified a new therapeutic principle for cancer cachexia.

Cancer cachexia affects 50 to 80 percent of all cancer patients, making it one of the most common complications of the disease. As cancer cells disrupt the body's metabolism, patients continue to lose weight and muscle mass even when eating sufficiently, leading to severe physical decline. This is a major reason chemotherapy often becomes less effective and treatment is discontinued, ultimately lowering survival rates. Existing drugs, however, have been limited to temporarily boosting appetite and have failed to fundamentally address the underlying muscle loss and metabolic dysfunction.

The research team focused on the idea that the root cause of cancer cachexia lies not in the body, but in the brain. The team noted that when GDF15 (Growth Differentiation Factor 15)-a signaling protein secreted in large amounts as cancer progresses-binds to GFRAL, a receptor protein in the brainstem, it triggers a signal instructing the body to stop eating and instead break down stored muscle and fat, driving progressive physical decline.

To block this process, the team worked with Professor Kim's group to develop a therapeutic using antisense oligonucleotides (ASO)-an RNA-based gene therapy technologies that selectively suppresses the activity of a specific gene-to prevent GFRAL from being produced in the first place.

In effect, the treatment switches off the receiver of the signal that cancer cells send instructing the body to waste away. By blocking GFRAL production at the RNA stage-the intermediate step in which genetic information is converted into protein-the therapy shuts down the cachexia-inducing signal at its source.

The team administered the treatment to mice in which cancer cachexia had already progressed. The result was a substantial reduction in muscle and fat loss, along with the restoration of the metabolic function that had previously broken down. Notably, even though treatment began after the disease had advanced significantly, survival at the study's endpoint (around day 50) was markedly higher in the treated group-90 percent-compared with just 20 percent in the untreated group, demonstrating the therapy's potential for treating cancer cachexia.

Unlike existing treatments that only stimulate appetite, this study is significant in that it blocks the underlying signal driving the wasting process itself. The therapy improved both muscle loss and metabolic dysfunction, and researchers expect that it could eventually be used alongside existing cancer treatments as a next-generation adjuvant therapy to improve patients' quality of life, treatment effectiveness, and survival rates.

"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," said Professor Song. He added that the team's goal is to move forward with follow-up preclinical research and drug manufacturing as well as quality-control systems without delay, begin clinical development in cancer patients by 2030, and develop the therapy into a treatment that improves patients' quality of life and survival rates.

Reference: Hong HJ, Lee MH, Park M, et al. Therapeutic Gfral silencing via antisense oligonucleotides ameliorates cancer-associated cachexia and extends survival in tumor-bearing mice. Cell Rep Med. 2026. doi: 10.1016/j.xcrm.2026.102939

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