Cancer-induced anorexia inspires potentially powerful antiobesity drug

Weight loss seems to come easiest to those who want it least. Every year, hundreds of thousands suffer from the loss of appetite that comes with tumor-induced anorexia, which can accompany many late-stage cancers. Now, researchers from three major pharmaceutical companies have independently published papers showing that the culprit behind this condition—a protein called growth differentiation factor-15 (GDF15)—helps mice, rats, and monkeys lose weight without any apparent side effects.

“The idea of having another medication to add to our armamentarium is exciting news,” says Katherine Saunders, an obesity medicine physician at Weill Cornell Medicine in New York City who was not involved with the work. There are currently five U.S. Food and Drug Administration–approved obesity medications for long-term weight management, which can help patients lose 5% to 8% of their body weight on average. “That’s very limited,” Saunders says, adding that many drugs used to treat obesity don’t have the same level of specificity as GDF15.

GDF15’s potential as a weight-loss agent was first discovered by Samuel Breit, an immunologist and physician at St. Vincent's Hospital in Sydney, Australia. He saw levels of the protein rise 10 to 100 times higher than normal during tumor-induced anorexia in mice with prostate tumors and in humans with advanced prostate cancer. Breit also showed that GDF15 likely exerts its effects through the brain—though he says that until now the protein’s target has befuddled scientists.

To find that target, Sebastian Beck Jørgensen, a diabetes and obesity researcher at Novo Nordisk in Maaloev, Denmark, and colleagues screened more than 2700 proteins that reside in human cell membranes, where they receive molecular signals from outside the cell and transmit their messages inward. Among all these possible partners, GDF15 bound to a single protein receptor called the GDNF family receptor α-like (GFRAL), whose function was previously unknown, the team reports this week in Nature Medicine .

Next, the researchers searched through an entire mouse brain for cells whose GFRAL gene was turned on. Surprisingly, it was found only in two regions of the brain: the area postrema, known as the “vomit-inducing center,” and the nucleus of the solitary tract, which houses neurons involved in many behaviors, including ones implicated in appetite regulation. That would normally be a problem for drug development, because most receptors are walled off by the blood-brain barrier, a system of cells that keeps drugs, toxins, and microbes out of the brain. But because these two GFRAL-containing regions are part of a small portion of the brain that sit outside the barrier, Jørgensen and colleagues think they’ve got a good drug target. “[It] turns out to not be as complicated as we were anticipating,” he says.

To prove that GFRAL was necessary for GDF15-powered weight loss, the team created a strain of mice that couldn’t produce the receptor, which they then compared with a group of regular mice. When fed a high-fat diet for 16 weeks, all the mice doubled in weight, from about 20 to 40 grams. Daily injection of GDF15 for 4 weeks reduced the regular mice’s food intake and thus helped them shed about 5 to 10 grams each, a significant fraction of their body weight. The mice without the GFRAL receptor didn’t lose any weight when given GDF15, but otherwise appeared similar to regular mice.

In another experiment with rats, a higher daily dose of GDF15 caused their food intake to plummet by 75%, from 20 to 5 grams of food per day. Rats whose diets were restricted to the same small portions of food—but who were not on GDF15—lost similar amounts of body weight and fat, which supports the idea that GDF15 works primarily by suppressing appetite, and not by boosting metabolism and burning calories.

Papers also published this week in Nature Medicine by Eli Lilly & Company in Indianapolis and Janssen BioTherapeutics in San Diego, California, also independently identified GFRAL as the receptor of GDF15, with similar diet-suppressing results. Additionally, Janssen researchers created a long-lasting version of GDF15 that was given to cynomolgus monkeys. It remained active in their bloodstream for 4 weeks and helped them drop 4% of their body weight.

“We are very glad to see the major findings in all three papers are consistent with each other,” says Xinle Wu, who led the research team at Eli Lilly. A spokesperson for Janssen declined an interview request.

One potential concern about GDF15 is that it acts on the vomit-inducing center of the brain. Janssen researchers noted no signs of nausea, uneasiness, or vomiting when GDF15 was given to monkeys. But Richard Palmiter, a neuroscientist who studies the regulation of appetite at the University of Washington in Seattle, says, “Since you can’t ask animals how they feel, there is a risk that this drug would make people feel sick rather than satiated.”

So far, Jørgensen says his team hasn’t noticed any side effects from GDF15, which can occur when a drug binds multiple targets, or when a receptor is found throughout the body. So far, GDF15 seems selective to GFRAL, which itself is highly localized to two small brain regions. He adds that Novo Nordisk is tweaking GDF15, ideally to exert a stronger and longer-lasting effect. This modified form of the protein is what will likely be tested in human clinical trials, whenever they occur: All three companies are hush-hush on time frames. Jørgensen anticipates a GDF15-based drug would be most effective in combination with existing or future obesity treatments.

W. Scott Butsch, an obesity medicine physician at Massachusetts General Hospital in Boston, agrees. (Butsch is part of Novo Nordisk’s clinician’s advisory board, but was not involved nor aware of its research on GDF15.) “Obesity is a complex disease with no one-size-fits-all treatment. Combination therapy is the future,” he says. For instance, GDF15, which dampens appetite, could be used additively or synergistically with another drug that boosts metabolism. “We’ve moved beyond thinking that one drug will win the jackpot and cure everyone’s obesity.”