The Chef’s Voice 

I was driving home from clinic on a rain-soaked Monday when I heard something that made me pull over and listen. It wasn’t about medicine or cancer or the patients I’d just spent the day treating. It was chef Matty Matheson, who plays Neal Fak on the acclaimed TV show “The Bear,” being interviewed by Kara Swisher. “Food is an uncompromising love,” he said, his voice crackling through my car speakers. “It’s a force that nourishes you, that you get to create, and it builds character.”

The History of Cachexia: A Long-Standing Challenge

For 2,500 years, since Hippocrates first described what we know today as cancer cachexia, we’ve witnessed this cruel phenomenon: cancer turning patients against food itself. Despite all our medical advances, we’ve mainly stood helpless as patients lost not just their desire to eat but, with it, their strength, their muscle mass, and often their ability to tolerate the very treatments that might save them.

The Path to Treatment

Over the years, we’ve tried various approaches to combat this condition. Medications like mirtazapine, megestrol acetate, steroids, cannabinoids, and olanzapine have shown some promise in increasing appetite and may lead to increased body weight. But their effects were limited by side effects, and more importantly, none succeeded in increasing muscle mass or physical activity—critical indicators of successful treatment.

The Biology of Cachexia

We now know that cancer cachexia isn’t simply about reduced food intake. At its roots, it is a complex metabolic rebellion, a state of increased inflammation orchestrated by tumor cells interacting with our immune system, internal organs, and brain centers. GDF-15, an inflammatory protein secreted by cancer cells, acts like a switch in the brain, simultaneously creating an aversion to food and accelerating metabolism—a perfect storm of physical decline.

The Breakthrough

A recent study published in the New England Journal of Medicine marks a turning point. Ponsegromab, a monoclonal antibody targeting GDF-15, has shown remarkable results: weight gain, improved muscle mass, and increased physical activity. In this randomized trial of 187 patients with advanced cancer, those receiving ponsegromab gained up to 2.8 kg compared to placebo, with improvements in appetite and physical activity. The effects lasted throughout the treatment, and side effects were minimal.

The Brain’s Role

The discovery illuminates an intricate network of appetite control centered in the brainstem. GDF-15, released by cancer cells and inflammatory tissues, binds to a specific receptor (GFRAL) in the brainstem. When GDF-15 levels rise during cancer, this activation triggers a cascade of neural signals through the brainstem to the hypothalamus, ultimately suppressing appetite and increasing energy expenditure. By blocking GDF-15, ponsegromab essentially releases this brake on appetite and metabolism.

A New Hope

Driving home that evening, I wondered about Matheson’s interview and my patients. For decades, our breakthroughs in oncology have focused on targeting cancer cells – through chemotherapy, immunotherapy, and targeted treatments. But this discovery represents a different kind of progress. By understanding and treating cancer’s metabolic effects, we’re addressing what patients and families struggle with daily: the ability to eat, maintain strength, and stay active. 

I thought of one of my patients, an avid tennis player in his early 70s, three months into his pancreatic cancer treatment. His once-fitted tennis shirt now hung loose, while his wife clutched a food diary documenting everything he wouldn’t eat. “If he only ate a little bit more,” she said. “Just a few bites.” 

This breakthrough may herald a new and long-awaited era in oncology, where extending life and preserving its quality advance hand in hand.