For the Kochanczyk family in Indiana, mealtime has always been a cherished family tradition. Dave Kochanczyk had a passion for barbecuing, preparing Polish dishes, and cooking fresh vegetables from his garden. When he wasn’t in the kitchen, he led a vibrant life as an electrical contractor and volunteer firefighter while managing his family’s expansive rural estate.
Major Trial Launched for Cancer Cachexia Treatment
Everything changed in 2010 when I was diagnosed with pancreatic cancer. Over the next seven years, despite undergoing intensive treatment, my love for food remained but my appetite drastically diminished. I lost muscle mass and became weakened, making it impossible to even chop wood for the house stove.
Kochanczyk’s battle was a result not only of the tumor but also of cachexia, a cancer-related syndrome characterized by loss of appetite and muscle wasting. “Watching my father struggle was incredibly difficult,” recalls his son Martin Kochanczyk. Since his father’s passing in 2017, Martin has become an advocate for cachexia awareness with the Cancer Cachexia Association, a community dedicated to advancing research, awareness, and treatment options.
Martin often stresses that his father’s experience isn’t an anomaly. “Cachexia impacts many cancer patients,” he explains. Estimates suggest that 50% to 80% of cancer patients experience cachexia, depending on the type and stage of the tumor.
“It’s like lying under a 1,000-pound blanket,” says Abigail Newell, senior director of research at the Cancer Support Community in Washington, D.C. “It feels like running a marathon just to sit there.” Moreover, cachexia is more than just a quality of life issue; it significantly affects survival rates. Fatigue, despair, and other psychological symptoms can hinder the motivation to continue treatment, with severe cachexia leading to treatment intolerance or exclusion from clinical trials. In fact, cachexia accounts for 20-30% of cancer-related deaths.
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Once assumed to be an inevitable aspect of cancer progression, cachexia is now a recognized research focus. In 2020, Cancer Grand Challenges, a global research initiative, invited scientists to propose cachexia-related projects.
The initiative funded an international collaboration involving 16 research teams across 14 sites, providing £20 million (US$25 million) to investigate cancer cachexia—its causes, subtypes, and potential treatments. Known as CANCAN, this project is now in its fifth year, producing around 30 academic papers and contributing to growing research efforts.
With an influx of new findings, the understanding of cachexia is evolving. Where researchers once viewed it purely as malnutrition and muscle loss, it is now recognized as a complex syndrome with disrupted metabolism. Research indicates that cachexia not only affects appetite and metabolism but also influences motivation and behavior. Several pharmaceutical companies, including Pfizer, are currently testing drugs to tackle cachexia, sparking hope for effective treatments on the horizon.
Source: Reference 10
“It remains a complex mystery,” says Ryan Schoenfeld, CEO of the Mark Cancer Research Foundation based in New York City. However, the recent surge in research has fostered optimism. “I’m confident that future research will yield treatments that will make cachexia more manageable than today,” he asserts. “Ideally, we’d like to prevent it altogether.”
Understanding Organ Crosstalk in Cachexia
Cachexia has often puzzled researchers. Despite its prevalence and significant impact on patients, it previously went unnoticed by many healthcare practitioners. Traditionally, experts focused on tumors, believing that removing cancer would resolve cachexia, Schoenfeld notes. Currently, approved treatments for cancer cachexia are scarce. Anamorelin, an appetite stimulant, is available in Japan, but the U.S. FDA and EU regulators have yet to approve it due to insufficient evidence of efficacy. Simply forcing individuals with this condition to eat more will not address the underlying problem.
As survivorship rates among cancer patients improve, the demand for effective cachexia treatments is expected to rise, prompting increased attention from funders and scientists. “A vibrant ecosystem of cachexia researchers has emerged,” states Tobias Janowitz, a physician-scientist at Cold Spring Harbor Laboratory in New York and co-principal investigator of CANCAN. Maryam Jamal Khanjani, a clinician-scientist at University College London and CANCAN co-investigator, adds that cachexia, once confined to niche discussions, is now gaining visibility in major oncology conferences like the American Association for Cancer Research’s annual meeting.
Andrea Bonnet, a muscle physiologist at the University of Colorado Anschutz in Aurora, has been studying cachexia since its early days. The evolution of understanding around this condition is remarkable. “Cachexia is not a singular gene or tissue disease; it’s multifaceted, involving multiple systems,” he explains. “Different organs can communicate signals that alter metabolism or influence cachexia pathways.”
The journey begins with cancer. When abnormal cells are detected, the immune system reacts, triggering inflammation. This process often leads to widespread signaling associated with cachexia. For instance, Bonnet’s research has shown that tumors that do not directly involve bone can still cause cell damage and bone loss.1 An antibody targeting RANKL—an important regulator of bone and muscle—as well as bisphosphonate drugs used in osteoporosis treatment may offer benefits in combating cachexia.
The liver also plays a pivotal role in cachexia signaling. Its secretions may exacerbate muscle and bone degradation. Biologist Mauricio Beriel Diaz from the Munich Helmholtz Center reported that liver cells react to cachexia by producing specific compounds.3 In lab studies, these compounds induced heart cell contractions and prompted fat breakdown. Notably, elevated levels were also found in individuals suffering from cachexia.3
In a mouse model of cachexia, researchers linked liver dysfunction to abnormalities in the vagus nerve, which communicates between the brain and multiple organs. Impairments in this nerve altered liver metabolism, creating a pro-inflammatory state related to cachexia. Blocking vagus nerve activity reduced weight loss and improved appetite and activity levels in mice.4
The Brain’s Role in Cachexia
Ultimately, the brain acts as the primary regulator of cachexia, according to neuroscientist Adam Kepex from Washington University in St. Louis, Missouri. This is the sole area where various inflammatory, metabolic, and hormonal elements of such a complex condition can converge. Consequently, cachexia involves both physical and psychological dimensions.
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The recent excitement around cachexia drug development ties back to GDF15, a stress hormone produced in the brain. GDF15 activates pathways that suppress appetite and produce feelings of fullness. If the body ingests something unsuitable, GDF15 signals to avoid it in the future. Although this hormone is known to contribute to cachexia-related appetite loss, its origins and role remain poorly understood.
Ming Li, a cancer biologist at the University of Oklahoma, and his team revealed GDF15’s involvement in the complex interactions among tumors, the brain, and the immune system. Tumor cells alone do not significantly induce cachexia in their models, but they do release signals that prompt immune cells to produce GDF15. Once GDF15 reaches the brain, it triggers signals back to the tumor, resulting in increased recruitment of immune cells, perpetuating a harmful cycle. Blocking or eliminating GDF15 has been shown to reduce cachexia symptoms in mice.5
While immune signals and associated inflammation are well-documented causes of cachexia, Kepex and colleagues discovered that certain immune molecules exert effects far beyond appetite modulation and physical wasting. Behavioral tests with cachexia-afflicted mice indicated that they were less inclined to expend energy to acquire food and water, revealing uncharacteristic apathy.6
Source: www.nature.com