Cancer-associated cachexia, a severe wasting syndrome that affects 50 to 80 percent of cancer patients, can now be targeted at its root cause in the brain using a new RNA-based therapeutic strategy developed by a KAIST research team. According to a KAIST announcement on August 2, researchers identified that blocking GFRAL receptors in the brainstem with antisense oligonucleotides prevents muscle and fat loss while significantly extending survival in tumor-bearing mice.
Targeting the Brain to Stop Muscle Wasting
Cancer cachexia causes patients to lose weight and muscle mass rapidly even when eating enough calories, due to metabolic disruptions driven by cancer cells. According to the research team, the root cause of this condition originates in the brain rather than the body. As cancer progresses, it secretes large amounts of a signaling protein called GDF15 (Growth Differentiation Factor 15). When GDF15 binds to GFRAL, a receptor protein in the brainstem, it triggers a biological signal that forces the body to stop eating and break down stored muscle and fat.
Existing treatments have been limited to temporarily boosting appetite. According to Professor Minho Shong, these older drugs fail to fundamentally address the underlying muscle loss and metabolic dysfunction. To counter this, the KAIST team worked with Professor Jinkuk Kim’s group from the Graduate School of Medical Science and Engineering to develop a gene therapy that shuts down the destructive signal at its source.
Did you know? Cancer cachexia is a major reason why chemotherapy often becomes less effective and treatment must be discontinued, ultimately lowering overall survival rates for patients.
RNA-Based Gene Therapy Using Antisense Oligonucleotides
The newly developed therapeutic uses antisense oligonucleotides (ASO), an RNA-based gene therapy technology that selectively suppresses the activity of a specific gene. According to the study, the ASO treatment prevents GFRAL from being produced in the first place by acting at the RNA stage, which is the intermediate step where genetic information is converted into protein.
“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,” Professor Shong said. By switching off the receiver of the signal that cancer cells send instructing the body to waste away, the therapy halts the degradation process.
Preclinical Trial Results and Survival Rates
The research team administered the ASO treatment to mice in which cancer cachexia had already progressed significantly. According to the findings published on July 27 in the international journal Cell Reports Medicine (DOI: 10.1016/j.xcrm.2026.102939), the treatment achieved a substantial reduction in muscle and fat loss and restored broken-down metabolic functions.
Even though treatment started after the disease had advanced, survival at the study’s endpoint around day 50 reached 90 percent in the treated group. By comparison, the untreated group recorded a survival rate of just 20 percent. The research was led by co-first authors Dr. Hyunjung Hong, Dr. Minhee Lee from THOR Therapeutics, and Dr. Minsung Park, with Professor Shong and Professor Kim serving as co-corresponding authors.
Researchers expect the therapy could eventually serve as a next-generation adjuvant therapy alongside existing cancer treatments to improve patients’ quality of life, treatment effectiveness, and survival rates. According to Professor Shong, the team aims to move forward without delay with follow-up preclinical research, drug manufacturing, and quality-control systems, with a goal to begin clinical development in cancer patients by 2030.
The study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government’s Ministry of Science and ICT (NRF-2023R1AC3003438). Additional funding was provided by grants from the Ministry of Health and Welfare (RS-2025-02262990) and the Ministry of SMEs and Startups (MSS) of the Republic of Korea (RS-2023-00239221).
Frequently Asked Questions
What causes cancer-associated cachexia?
Cancer-associated cachexia is caused by cancer cells disrupting metabolism and secreting GDF15, a signaling protein that binds to GFRAL receptors in the brainstem and signals the body to break down muscle and fat.
How does the new KAIST therapy work?
According to the research team, the therapy uses antisense oligonucleotides (ASO) to prevent the production of GFRAL receptors in the brainstem at the RNA level, blocking the wasting signal from cancer cells.
When will human clinical trials begin?
Researchers aim to begin clinical development of the therapy in cancer patients by 2030, following upcoming preclinical research and drug manufacturing preparations.
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