Cancer Cell Publication Details Development of Cancer-Induced Cachexia and Anorexia

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OKLAHOMA CITY – New research from the University of Oklahoma, published today in Cancer Cell, describes for the first time a “triangle regulation theory” of cancer-induced cachexia and anorexia.

Cachexia is a muscle-wasting and fat-loss condition that most often occurs in people diagnosed with pancreatic cancer. Cachexia is frequently accompanied by cancer-induced anorexia, a severe loss of appetite that adds to the patient’s debilitation.

OU College of Medicine Professor Min Li, Ph.D., led a team of researchers who discovered another piece of the puzzle in how cachexia and anorexia develop. In their triangle regulation theory, the cancer cells recruit and activate macrophages (a type of immune cell), which, in turn, enlist the involvement of the central nervous system. That three-part cascade of events triggers excess production of growth and differentiation factor 15 (GDF15), which is known to be elevated in people with cachexia.

“These actions represent a vicious cycle that drives the progression of cachexia and the suppressed appetite of anorexia. GDF15 is the key player. It involves the central nervous system because the receptor for GDF15 is in the brainstem,” said Li, associate director for global oncology for OU Health Stephenson Cancer Center.

Robert Mannel, M.D., director of the OU Health Stephenson Cancer Center, said, “Dr. Li’s work has created a paradigm shift in our understanding of cancer cachexia and is critical in developing new therapeutic strategies.”

Because patients with cachexia and anorexia are so weak, their ability to withstand aggressive treatment for pancreatic cancer is greatly reduced. There are no good treatments for cachexia, nor does nutritional support reverse the symptoms.

“Eight out of 10 patients with pancreatic cancer develop cachexia,” Li said. “It doesn’t happen with every type of cancer; people with brain tumors or breast cancer, for example, tend not to lose body weight. We believe our research contributes to the search for a cachexia treatment, which would help pancreatic cancer patients better tolerate treatment like chemotherapy.”

In this study, Li and his team also tested an antibody for its ability to neutralize or block the production of GDF15. In mice, the antibody was effective in reducing the symptoms of cachexia and anorexia. Pharmaceutical companies are also developing antibodies to target cachexia, and a Phase 3 clinical trial is underway, Li said.

Li’s research has evolved to a more sophisticated understanding of the cause of cachexia. In a 2024 paper also published in Cancer Cell, he discovered that “crosstalk” between pancreatic cancer cells and macrophages is the first step toward the onset of cachexia. In his current paper, the involvement of the central nervous system creates the triad of actions responsible for the onset of cachexia.

“Our research will continue because this whole process is very dynamic,” he said. “The three ‘players’ of the triangle regulation can change over time, and there may be multiple triangles working together. We’re very excited about what we will continue to find.”