Blocking Tumor-Derived Protein Halts Cachexia in Preclinical Study


Key Points

  • Parathyroid hormone–related protein (PTHrP) stimulates brown fat cells mixed with stored white fat in the body, causing the white fat to generate heat and cause weight loss.
  • Administering a polyclonal antibody that neutralizes PTHrP prevented cachexia almost completely in cachexic mice with lung tumors.
  • The antibody treatment also prevented the loss of muscle mass and improved muscle function.

New research raises the prospect of more effective treatments for cachexia, a profound wasting of fat and muscle occurring in about half of all cancer patients, raising their risk of death, according to scientists from Dana-Farber Cancer Institute. In a study reported in Nature, Spiegelman et al demonstrated that symptoms of cachexia improved or were prevented in mice bearing lung tumors when they were given an antibody that blocked the effects of the parathyroid hormone–related protein (PTHrP), which is secreted by many types of cancer cells.

Patients with upper gastrointestinal and pancreatic cancers are the most likely to develop cachexia, and the condition affects about 80% of terminal cancer patients. The current strategy to combat cachexia is to give appetite stimulants and nutrient supplements, along with medications to counteract some of the molecular pathways believed to underlie the wasting process, but it has had limited success.

Preclinical Study

The scientists said their findings are the first to explain in detail how PTHrP from tumors switches on a thermogenic process in fatty tissues, resulting in unhealthy weight loss. This tumor-derived protein, they found, stimulated brown fat cells mixed with stored white fat in the body, causing the white fat to “brown”—that is, generate heat and cause weight loss even when the animals were at rest.

The researchers carried out two experiments using mice that developed lung tumors and cachexia. In one, they administered a polyclonal antibody that specifically neutralizes PTHrP and found that it prevented the wasting almost completely, while untreated animals became mildly cachexic.

In a second experiment, the antibody treatment prevented the loss of muscle mass and improved muscle function, while control animals developed severe muscle-wasting.

“You would have expected, based on our first experiments in cell culture, that blocking PTHrP in the mice would reduce browning of the fat,” said Dr. Spiegelman. “But we were surprised that it also affected the loss of muscle mass, and improved health.”

Piece of the Puzzle

The research suggested that PTHrP alone doesn’t directly cause muscle wasting, yet blocking the protein’s activity prevents it. Thus, the role of PTHrP “is definitely not the whole answer” to the riddle of cachexia, noted Dr. Spiegelman, but may be a necessary part, while other factors are also involved.

It may turn out that the PTHrP mechanism is responsible for cachexia in a subset, but not all, cancer patients, Dr. Spiegelman suggested. Before trying the anti-PTHrP antibody in human patients, he said, “clinicians would probably first want to find out if the protein is elevated in certain cancers, and determine which patients would be good candidates for a clinical trial.”

Barrett Rollins, MD, PhD, Dana-Farber’s Chief Scientific Officer, commented that the report from Dr. Spiegelman and his colleagues “provides a new roadmap for developing a rational, mechanistically based treatment for this incredibly debilitating condition that occurs in such a large number of our patients. Until now we’ve had no truly effective way to reverse this horrible complication.”

Dr. Spiegelman is the corresponding author for the Nature article.

The study was supported by a grant from the National Institutes of Health. Serkan Kir, PhD, is a Robert Black Fellow of the Damon Runyon Cancer Research Foundation.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.