Contact: Teresa Herbert
Dana-Farber Cancer Institute
Antibody halts cancer-related wasting condition
Study pinpoints a molecular cause of cachexia, and hints at a
BOSTON – 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.
Many strategies have been tried to reverse the condition, which may
cause such frailty that patients can’t endure potentially life-
saving treatments, but none have had great success.
Scientists reporting in the July 13 advanced online edition of
Nature, led by Bruce Spiegelman, PhD, demonstrated that in mice
bearing lung tumors, their symptoms of cachexia improved or were
prevented when given an antibody that blocked the effects of a
protein, PTHrP, secreted by the tumor cells. PTHrP stands for
parathyroid hormone-related protein, and is known to be released
from many types of cancer cells.
The scientists said their findings are the first to explain in
detail how PTHrP from tumors switches on a thermogenic (heat-
producing) process in fatty tissues, resulting in unhealthy weight
This tumor-derived protein, they found, stimulated “beige” or 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 Spiegelman. “But we were surprised that it also
affected the loss of muscle mass, and improved health.”
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 Spiegelman, but may be a necessary part,
while other factors are also involved.
A collaborator on the study, Vickie E. Baracos, PhD, at the
University of Alberta in Edmonton, Canada, provided the blood of 47
patients with lung or colon cancer who were cachexic. Serkan Kir,
PhD, from the Spiegelman lab – and first author on the paper –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 were the other patients in the group.
It may turn out that the PTHrP mechanism is responsible for
cachexia in a subset, but not all, cancer patients, 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 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.”
Patients with upper gastrointestinal and pancreatic cancers are the
most likely to develop cachexia, and the condition affects about 80
percent of terminal cancer patients. Current strategy 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 with limited success.