Mealtimes were always a family affair for the Kochanczyks of Indiana. Dave Kochanczyk loved barbecuing, cooking Polish fare and preparing fresh vegetables from the garden. When not in the kitchen, he led an active life: working as an electrical contractor, serving as a volunteer firefighter and managing the family’s large country property.

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That all changed after he was diagnosed with pancreatic cancer in 2010. Over the next seven years, as he endured intensive treatment, his love of food remained but his appetite dwindled. He lost muscle mass and became gaunt. Weakened and fatigued, he could no longer chop wood for the home’s stove.

Kochanczyk’s struggles were not only the result of the tumour and treatments waging war against one another in his body, but also due to cachexia, a cancer-linked syndrome that causes reduced appetite and muscle wasting. “It’s very hard to watch,” recalls Dave’s son Martin Kochanczyk. Since his father’s death in 2017, Martin has become an advocate for cachexia awareness with the Cancer Cachexia Society, a community of scientists, people with the condition and others advancing research, awareness and treatment.

As Martin often explains to people with cancer and their families, his father was hardly an outlier. “Cachexia affects a lot of people,” he says. Between 50% and 80% of people with cancer, depending on the tumour type and disease stage, experience cachexia.

“I’ve heard people describe it as lying down under a thousand-pound blanket,” says sociologist Abigail Newell, senior director of research at the Cancer Support Community in Washington DC. “Sitting up feels like running a marathon.” And it’s more than a quality-of-life issue; cachexia affects survival. Exhaustion, hopelessness and other psychological symptoms can make people less willing to keep up with treatments. Severe cachexia can even make some therapies intolerable, or cause individuals to be excluded from clinical trials. Ultimately, 20–30% of cancer-associated deaths are attributable to cachexia, rather than the cancer itself.

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Although cachexia was long considered an inescapable part of cancer’s progression, it has now become a topic of study in its own right. In 2020, a global research initiative, Cancer Grand Challenges, asked scientists to propose projects on cachexia.

The initiative ended up funding an international team of clinicians, scientists and advocates — 16 research groups across 14 institutions — to the tune of £20 million ($US25 million) to study cancer cachexia, its drivers, subtypes and potential treatments. Now in its fifth year, the project, known as CANCAN, has released about 30 papers, which have appeared alongside a rising tide of research from independent efforts.

With the influx of fresh studies, the very concept of cachexia is changing. Where scientists once saw simple malnutrition, muscle wasting and weight loss, they now see a whole-body syndrome of metabolism gone haywire. Studies reveal how cachexia is more than physical symptoms; it affects not just appetite and metabolism, but also motivation and behaviour. And a handful of companies, including pharmaceutical giant Pfizer, are testing medicines for cachexia (see ‘Fighting cachexia’), raising hope that a treatment might be on the horizon.

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“It’s still an area of mystery,” says Ryan Schoenfeld, chief executive of the Mark Foundation for Cancer Research in New York City, a grant-making organization. But the burst of activity over the past few years has made him optimistic. “I feel confident in the future of the research here, that we’ll uncover ways to treat cachexia that will make it more reversible than it is today,” he says. “Ideally, we’ll prevent it.”

Organ crosstalk

Cachexia has long been something of a paradox in cancer: widely prevalent and with a huge impact on people, it nevertheless existed beyond the gaze of many physicians and scientists. Specialists typically focused on the tumour, reasoning that eliminating the cancer would relieve the cachexia, says Schoenfeld. There are no approved medications for cancer cachexia in most parts of the world. The appetite stimulant anamorelin is available in Japan, but the US Food and Drug Administration and the European Medicines Agency found the evidence for its benefits to be insufficient for approval. Even if people with the condition force themselves to eat more, or are fed through a tube, it doesn’t solve the problem.

With more people surviving for longer with cancer, the need for cachexia treatment is only growing, and funders and scientists have taken note. “There’s a whole ecosystem of cachexia researchers now,” says Tobias Janowitz, a physician-scientist at Cold Spring Harbor Laboratory in New York and co-principal investigator of CANCAN. Once a specialist topic relegated to niche conferences, cachexia has been on the programme of the annual meeting of the American Association for Cancer Research for the past several years, notes Mariam Jamal-Hanjani, a clinician-scientist at University College London and a CANCAN co-investigator.

Andrea Bonetto, a muscle physiologist at the University of Colorado Anschutz in Aurora, has been studying cachexia since before the field took off. When he began, the condition was considered mainly a case of muscle wasting. “What is now clear, compared to 24 years ago, is that cachexia is not a single gene, a single-tissue disease, but it’s multifaceted, it’s multi-tissue, it’s multi-systemic,” he says. “There’s huge crosstalk among different tissues and organs.” Each region of the body might receive signals that cause it to alter its metabolism or activities, and to send signals that influence cachexia pathways in other parts.

The path starts with the cancer. The immune system might respond to the presence of abnormal cells, resulting in inflammation. But cachexia-associated signalling spreads widely. Bonetto’s group found, for example, that tumours that neither originate in nor infiltrate bone can, nonetheless, cause cell death and breakdown in bones1. Antibodies that block a regulator of bone remodelling and muscle structure called RANKL, which is made by bone and by several tumour types, minimized bone and muscle loss and preserved strength in a mouse model of ovarian cancer2. Bisphosphonate drugs used to treat osteoporosis had similar benefits, suggesting that these medications might have a place in treating cachexia, too.

The liver also seems to have a key role in cachexia signalling. For one, its secretions seem to worsen the breakdown of muscle and bone, Bonetto says. A contribution from this organ makes sense, says Mauricio Berriel Diaz, a biologist at the Helmholtz Centre Munich in Germany, because the liver is a major regulator of metabolism. He and his colleagues reported that liver cells respond to cachexia by secreting a handful of specific compounds3. In lab dishes, these compounds cause heart cells to shrink and fat cells to break down fat. Levels of these secretions were also elevated in people with cachexia3.

Another study, in mouse models of cachexia, linked liver problems to the vagus nerve, which runs between the brain and other organs. Vagus dysfunction caused the liver to alter its metabolism, adopting a pro-inflammatory, cachexia-promoting state. Blocking vagal activity minimized weight loss and improved appetite and activity level in these mice4.

A disease of the brain

The brain ultimately becomes a key orchestrator of cachexia, says Adam Kepecs, a neuroscientist at Washington University in St. Louis, Missouri. It is the only place in the body that can integrate the various inflammatory, metabolic and hormonal elements of such a complex condition, Kepecs says. And it’s where cachexia becomes not just physical, but also psychological.

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Right now, much of the excitement around drug development for cachexia has to do with the action of the stress hormone GDF15 in the brain. GDF15 activates a signalling pathway that diminishes appetite and creates a sense of satiety. If you eat something that doesn’t agree with you, GDF15 sounds the alarm, so you don’t eat it again. The hormone is a well-known contributor to the appetite loss seen in cachexia, but scientists don’t fully understand where it comes from or how it participates in the condition.

At the University of Oklahoma in Oklahoma City, cancer biologist Min Li and his colleagues have identified GDF15’s role in a three-way conversation between the tumour, the brain and the immune system. Tumour cells alone don’t cause much cachexia in the mice that he and his colleagues used, Li says. But they release signals that cause immune cells to produce GDF15. When GDF15 reaches the brain, the brain then signals back to the tumours, causing them to recruit further immune cells. These then become additional GDF15 producers, creating a vicious cycle. Eliminating or blocking GDF15 reduced cachexia in the mice5.

Immune signals and the inflammation they cause are well-known contributors to cachexia, but Kepecs and his colleagues found that at least one immune molecule has an influence well beyond affecting appetite and wasting. When the researchers did behavioural tests on mice with cachexia, they found that the animals were less likely to put in extra effort to obtain food or water — even beyond expectations for mice with low appetite and reduced energy levels6. They seemed to have low motivation.