New Clues to Causes of Cachexia

Recent research has provided new clues to the causes of cachexia. In one, an animal study now online ahead of print in Nature (doi:10.1038/nature13528), symptoms of cachexia improved or were prevented when mice were given an antibody that blocked the effects of the parathyroid hormone-related protein (PTHrP), known to be secreted by tumor cells. The researchers, led by Bruce Spiegelman, PhD, the Stanley J. Korsmeyer Professor of Cell Biology and Medicine at Harvard Medical School and Dana-Farber Cancer Institute, said the findings are the first to explain in detail how PTHrP switches on a thermogenic process in fatty tissues, resulting in unhealthy weight loss. This tumor-derived protein stimulated “beige” or brown fat cells mixed with stored white fat in the body, causing the white fat to brown—that is, to generate heat and cause weight loss even when the animals were at rest. The team carried out two experiments with mice that developed lung tumors and cachexia. In one, a polyclonal antibody that specifically neutralizes PTHrP almost completely prevented cachexia, while untreated animals became mildly cachexic. In the 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,” Spiegelman said in a news release. “But we were surprised that it also affected the loss of muscle mass, and improved health.” The research suggests that PTHrP alone does not directly cause muscle wasting, yet blocking the protein's activity prevents it, he explained. Thus, the role of PTHrP “is definitely not the whole answer” to the riddle of cachexia, but may be a necessary part, while other factors are also involved. He said that before trying the anti-PTHrP antibody in humans, “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.” The first author of the study is Serkan Kir, PhD, of the Spiegelman lab and Robert Black Fellow at the Damon Runyon Cancer Research Foundation. Barrett Rollins, MD, PhD, Dana-Farber's Chief Scientific Officer, said the report “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.” The current strategy, he noted, 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 those have only limited success. Another study, by an international team of researchers and now online in Cell Metabolism (doi.org/10.1016/j.cmet.2014.06.011), found evidence that brown fat is key to the process of cachexia. The team, led by Erwin Wagner, PhD, of the National Cancer Research Centre in Madrid, found that in mice and patients with cancer-associated cachexia, white fat undergoes significant changes and turns into calorie-burning brown fat. The transformation leads to increased energy consumption and organ-wasting. Inflammation was also found to play an important role in turning white fat into brown fat during cancer-associated cachexia, which suggests a potential therapeutic target, the researchers said in a news release. Anti-inflammatory therapies, including the nonsteroidal anti-inflammatory drug sulindac, ameliorated the severity of cachexia in mice. “Our data suggest that inhibition of the browning of white fat represents a promising approach to ameliorate the severity of cachexia in cancer patients,” Wagner said. “In addition, identifying biomarkers of browning at early stages of cancer development could help to predict which patients are going to develop cachexia and would thus be good candidates to benefit from a preventive treatment.” iPad Extra!FigureWATCH: In a video on the iPad edition of this issue created by the Spanish National Cancer Research Centre, see more about the clinical significance of the findings and the strategy that may stimulate weight gain and muscle strength.FigureTo receive our iPad issues, download the free Oncology Times app from the App Store today! Visit http://bit.ly/OT-iPadApp, search in the App Store, or follow the link on oncology-times.com.