Cancer-associated cachexia, the wasting syndrome that erodes muscle, fat and physical resilience in many people with advanced cancer, has long resisted treatment. Now, researchers at the Korea Advanced Institute of Science and Technology (KAIST) report a preclinical strategy that targets the disorder from an unexpected location: the brainstem. In tumor-bearing mice, an RNA-based therapy designed to silence a neural receptor preserved body weight, muscle mass, fat stores and physical function, while dramatically improving survival even after cachexia had already developed.

The study was conducted by a joint team led by Minho Shong and Jinkuk Kim of KAIST’s Graduate School of Medical Science and Engineering, in collaboration with the KAIST faculty startup THOR Therapeutics. Their approach focuses on the biological circuit formed by growth differentiation factor 15, or GDF15, and its receptor, GFRAL. GDF15 is a signaling protein released in elevated amounts during several disease states, including cancer. When it reaches the hindbrain and binds to GFRAL, it activates neural pathways associated with nausea, appetite suppression and profound metabolic changes.

Cachexia is more complex than ordinary weight loss. Patients can continue losing muscle and body fat even when food intake is adequate, because cancer and the host response to cancer disrupt the systems that regulate energy use, inflammation and tissue maintenance. The resulting decline can weaken immunity, reduce mobility and make chemotherapy more difficult to tolerate. Although the syndrome affects an estimated 50 to 80 percent of people with cancer, available treatments have generally focused on stimulating appetite or providing nutritional support. Such measures may increase food intake temporarily, but they do not necessarily halt the breakdown of muscle or correct the underlying metabolic disturbance.

The KAIST researchers reasoned that the GDF15–GFRAL pathway could act as a central command system for this wasting response. GDF15 produced in the body circulates to the brainstem, where GFRAL is concentrated in a specialized region known as the area postrema and its surrounding neural circuitry. Once activated, this receptor can influence brain networks that control feeding behavior and autonomic metabolism. Rather than attempting to neutralize GDF15 throughout the body, the team chose to disable the receptor itself in the brainstem, preventing the signal from being received.

To accomplish this, the researchers developed antisense oligonucleotides, or ASOs, directed against Gfral messenger RNA. ASOs are short, chemically modified strands of nucleic acid engineered to bind a specific RNA sequence. When an ASO binds its target messenger RNA, cellular enzymes can promote its degradation or interfere with its processing, reducing production of the corresponding protein. In this case, the treatment lowered the supply of GFRAL receptors in the brainstem. The strategy therefore acts at the RNA stage, before the receptor is assembled and displayed on the surface of neural cells.

The experiments were performed in mice carrying tumors and showing established signs of cancer cachexia. This timing is important because many experimental interventions appear effective only when administered before severe wasting begins. According to the researchers, GFRAL silencing after cachexia had progressed substantially reduced the loss of muscle and fat. Treated animals also showed restoration of metabolic functions that had deteriorated during tumor growth, suggesting that the intervention did more than increase appetite. It helped interrupt the physiological program driving the breakdown of energy reserves.

The most striking result involved survival. At approximately day 50, the endpoint used in the study, about 90 percent of the mice receiving the GFRAL-targeting ASO remained alive, compared with roughly 20 percent of untreated tumor-bearing animals. The treated mice retained greater body weight and muscle mass and performed better in measures of muscle function. These findings indicate that cachexia itself can be a major determinant of outcome in cancer-bearing organisms and that blocking its central signaling pathway may provide benefits beyond nutritional improvement.

The work does not yet establish whether the same treatment will be safe or effective in people. GFRAL signaling is involved in the body’s response to circulating stress signals, and manipulating a receptor in the brainstem requires careful assessment of neurological, cardiovascular, gastrointestinal and metabolic effects. Human cancers also vary widely in their production of GDF15, tumor location and inflammatory biology. Nevertheless, the results offer a mechanistically precise alternative to therapies that merely encourage patients to eat. By targeting the receptor rather than broadly suppressing the signaling protein, the ASO approach may eventually be combined with chemotherapy, immunotherapy or other cancer treatments.

The findings, published in Cell Reports Medicine, represent an early step toward translating a brain-directed RNA therapy for cachexia. The researchers plan further preclinical studies, along with development of manufacturing and quality-control systems, with the stated goal of beginning clinical development in cancer patients by 2030. If the biology can be reproduced safely in humans, silencing GFRAL could become an adjunct treatment intended to preserve physical function, extend treatment tolerance and improve survival. For now, however, the evidence remains limited to tumor-bearing mice, and the central challenge will be determining whether a signal that can be switched off experimentally can be controlled with equal precision in patients.

Subject of Research:
An antisense oligonucleotide therapy targeting brainstem GFRAL to treat cancer-associated cachexia in tumor-bearing mice.

Article Title:
Therapeutic Gfral silencing via antisense oligonucleotides ameliorates cancer-associated cachexia and extends survival in tumor-bearing mice

Web References:
https://doi.org/10.1016/j.xcrm.2026.102939

References:
Cell Reports Medicine, published 27 July 2026. DOI: 10.1016/j.xcrm.2026.102939

Image Credits:
KAIST

Keywords:
Cancer cachexia, GFRAL, GDF15, antisense oligonucleotides, RNA therapy, brainstem, muscle wasting, cancer metabolism, preclinical research, KAIST

A protein known for circulating in the blood to fight infection plays a very different role when produced by cells inside tumors. A protein that emerged long before animals developed circulatory systems may influence whether cancer immunotherapy succeeds. Researchers at Nagoya University in Japan found that complement C3 helps keep immunosuppressive cells out of tumors, [...]

An unexpected transmissible cancer has been detected in North American waterways, prompting new concerns about how the disease developed.

Beginning with discoveries in Lake Memphremagog, a glacial lake spanning both Quebec and Vermont, researchers have found strange black cancerous lesions on fish in the waterways of New England and Canada, revealing an environmental mystery.

University of Vermont researchers announced the startling cancer discovery in a recent paper published in Nature, describing how the cells act similarly to a parasite, transmitting between hosts.

This discovery marks the first time a freshwater species has been identified as afflicted with a transmissible cancer, whose long-term population effects are a major concern.

Fish Cancer

Many questions swirl around this discovery, which go far beyond the specific locations and even species affected—such as how cancer operates and how this transmissible form could have originated.

The first indications that something was amiss came from anglers and biologists who both noticed more brown bullhead catfish with raised black patches coming out of Lake Memphremagog. From their first identifications in 2012 to 2014, the prevalence of the disease increased to one in three of these fish.

These particular catfish are often used as a barometer for environmental health, leading the University of Vermont team to consider a pollution-related pathogen after they had ruled out a viral one. Yet under close examination, they discerned the lesions were something even less expected: a type of skin cancer called melanoma, typically caused by sunlight, and therefore, exceedingly rare in bottom-dwelling fish.

Genetic Research

The melanoma finding set the team on a research course looking to identify whether a genetic mutation had left this catfish population particularly susceptible to skin cancer. What they found was surprising: these cancer cells were more closely related to one another than to their host fish’s healthy cells, suggesting transmission.

These transmissible cancers are extremely unusual, with only three types having been discovered previously. None have been found in freshwater or fish species before this; they have been relegated to Tasmanian devils, dogs, and mollusks.

So far, researchers have only identified the malady in larger, spawning-age fish, leading the team to suspect that transmission occurs during spawning behavior. These events do appear to be a likely candidate, as the fish cluster tightly together in shallow water, providing ample opportunity for physical contact among many fish. Furthermore, due to their lack of scales and bottom-dwelling nature, they are more susceptible to the sediment, which could harbor free-floating cancer cells.

In other species, these transmissible cancers may or may not have devastating population-scale effects. Currently, how the Lake Memphremagog catfish population will fare is unknown, although some fish appear to survive years after the infection is first noted.

The University of Vermont team says that the cancer cannot affect humans, and the lake’s drinking water is safe, but they would caution against eating the cancerous fish.

The Root of Cancer

While the Coventry Landfill is in close proximity to the lake, the cancer is spread evenly along the 32-mile-long lake, instead of concentrating near the landfill. Additionally, water tests show that contamination levels are no higher than those of similar North American waterbodies such as Lake Champlain.

Instead, more concerning than a single source of pollution, the team says they have now discovered this cancer in fish located in other ponds and lakes in this region, none of which were close to pollution sources and had pristine water quality.

The one correlation identified so far is that the cancer cells have high arsenic levels, an element naturally found in the region’s soil in high concentrations. Along with this possible link to a natural cause, the researchers are beginning to suspect that the cancer has existed for quite some time, but has simply gone unrecognized. A potential line of evidence for this hypothesis comes from the journals of Henry David Thoreau, who noted a catfish with a similar condition back in the summer of 1852. He even noted that he had come across the fish disease previously, and again wrote of it in 1858.

“By studying how cancers survive and spread outside their original host, we can learn a great deal about what keeps cancers contained—and what happens when those boundaries break down,” co-author Julie Dragon concluded. “These fish provide an opportunity to look at the evolution of cancer.”

The paper, “Brown Bullhead Catfish Melanoma Represents a Novel Transmissible Cancer,” appeared in Nature on July 22, 2026.

Ryan Whalen covers science and technology for The Debrief. He holds an MA in History and a Master of Library and Information Science with a certificate in Data Science. He can be contacted at ryan@thedebrief.org, and follow him on Twitter @mdntwvlf.