Preclinical research raises the prospect of more effective treatments for cachexia, a profound wasting of fat and muscle that can increase the risk of death in cancer patients.
In mouse models, an antibody effectively improved or prevented symptoms of cachexia.
The antibody inhibited the effects of parathyroid hormone-related protein (PTHrP), which is released from many types of cancer cells.
The researchers said their findings, published in Nature, are the first to explain in detail how PTHrP from tumors switches on a thermogenic process in fatty tissues, resulting in unhealthy weight loss.
The team carried out 2 experiments using mice that developed lung tumors and cachexia. In the first, a polyclonal antibody that specifically neutralizes PTHrP prevented cachexia almost completely, while untreated animals became mildly cachexic.
Anti-PTHrP treatment prevented the shrinkage of fat droplets. It blocked thermogenic gene expression in epididymal white adipose tissue, interscapular brown adipose tissue, and inguinal white adipose tissue, which suggests thermogenesis has a causal role in fat wasting.
Treatment with the anti-PTHrP antibody also lowered oxygen consumption in the mice, increased their physical activity, and reduced their heat production.
In the second experiment, the researchers treated mice with the anti-PTHrP antibody until they observed severe cachexia in control animals. The antibody significantly preserved muscle mass, which was evident by improved grip strength and in situ muscle contraction.
“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 study author Bruce Spiegelman, PhD, of the Dana-Farber Cancer Institute in Boston.
“But we were surprised that it also affected the loss of muscle mass and improved health.”
Additional experiments, in which the researchers injected PTHrP into healthy and tumor-bearing mice, suggested that PTHrP alone doesn’t directly cause muscle wasting. But blocking the protein’s activity still prevents cachexia.
Thus, the role of PTHrP “is definitely not the whole answer” to the riddle of cachexia, Dr Spiegelman noted. Furthermore, it may turn out that the PTHrP mechanism is responsible for cachexia in only a subset of cancer patients.
The researchers analyzed blood samples from 47 cachexic patients with lung or colon cancer. And they found increased levels of PTHrP in 17 of the patients. Those patients had significantly lower lean body mass and were producing more heat energy at rest than the other patients in the group.
Dr Spiegelman noted that, before they test the anti-PTHrP antibody in clinical trials, clinicians would likely want to determine if the protein is elevated in certain cancers and determine which patients would be good candidates for the treatment.
