Silencing a brain receptor curbs cancer cachexia and boosts mouse survival
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.
A KAIST research team has discovered a novel approach to combating cancer-related cachexia—a debilitating condition that causes significant muscle and fat loss in cancer patients. The team, led by Professor Minho Shong and Professor Jinkuk Kim from KAIST's Graduate School of Medical Science and Engineering, in collaboration with KAIST faculty startup THOR Therapeutics, identified a new therapeutic strategy targeting a brain signal involved in the progression of cancer cachexia.
The study focused on GDF15, a signaling protein produced by cancer cells, and its interaction with GFRAL, a receptor protein located in the brainstem. When GDF15 binds to GFRAL, it triggers a signal that instructs the body to stop eating and instead break down stored muscle and fat to fuel the growing tumor. This process, known as cancer-associated cachexia, affects up to 80% of cancer patients and is a major reason why chemotherapy often fails to work and why patients discontinue treatment, ultimately leading to reduced survival rates.
To prevent this process, the research team developed an RNA-based therapeutic using antisense oligonucleotides (ASO), a gene therapy technology that selectively inhibits the production of specific genes. By preventing the production of GFRAL, the therapy effectively blocks the brain signal that drives cachexia. The team administered the treatment to mice with advanced cancer cachexia, and the results were striking.
The treatment significantly reduced muscle and fat loss, restored metabolic function, and notably increased survival rates—90% of treated mice survived until the study's endpoint (around day 50), compared to just 20% of untreated mice.
This groundbreaking therapy represents a new approach to cancer cachexia by targeting the underlying cause—rather than simply addressing symptoms like appetite loss. The approach holds promise for improving treatment outcomes, enhancing patients' quality of life, and potentially extending survival rates. Professor Shong emphasized the significance of this study, noting that it marks a major step forward in developing adjuvant therapies to complement existing cancer treatments.
The team plans to move forward with preclinical research, drug manufacturing, and clinical development, with the goal of bringing this innovative therapy to cancer patients by 2030.
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