HOUSTON — Obese rhesus monkeys lost on average 11 percent of their
body weight after four weeks of treatment with an experimental drug that
selectively destroys the blood supply of fat tissue, a research team led by
scientists at The University of Texas MD Anderson Cancer Center reports in
Science Translational Medicine.
Body mass index (BMI) and abdominal
circumference (waistline) also were reduced, while all three measures were
unchanged in untreated control monkeys. Imaging studies also showed a
substantial decrease in body fat among treated animals.
this compound for human use would provide a non-surgical way to actually reduce
accumulated white fat, in contrast to current weight-loss drugs that attempt to
control appetite or prevent absorption of dietary fat,” said co-senior author
Renata Pasqualini, Ph.D., professor in MD Anderson’s David H. Koch Center for
Applied Research of Genitourinary Cancers.
Previous attempts to treat
obesity have predominantly focused on drugs aimed at suppressing appetite or
increasing metabolism, the researchers noted, but these efforts have been
hampered by their toxic side-effects. The MD Anderson group designed a new drug,
which includes a homing agent that binds to a protein on the surface of
fat-supporting blood vessels and a synthetic peptide that triggers cell death.
Their blood supply gone, fat cells are reabsorbed and
“Obesity is a major risk factor for developing cancer,
roughly the equivalent of tobacco use, and both are potentially reversible” said
co-senior author Wadih Arap, M.D., Ph.D., also professor in the Koch Center.
“Obese cancer patients do worse in surgery, with radiation or on chemotherapy –
worse by any measure.”
Monkeys are spontaneously obese In earlier
preclinical research, obese mice lost about 30 percent of their body weight with
the drug, now called Adipotide. The drug acts on white adipose tissue, the
scientific name for the unhealthy type of fat that accumulates under the skin
and around the abdomen, and is a disease and mortality predictor.
drugs against obesity fail in transition between rodents and primates,”
Pasqualini said. “All rodent models of obesity are faulty because their
metabolism and central nervous system control of appetite and satiety are very
different from primates, including humans. We’re greatly encouraged to see
substantial weight loss in a primate model of obesity that closely matches the
The rhesus monkeys in the current study were
“spontaneously” obese, said study first author Kirstin Barnhart, D.V.M, Ph.D., a
veterinary clinical pathologist at MD Anderson’s Keeling Center for Comparative
Medicine and Research in Bastrop, Texas. No specific actions were taken to make
them overweight; they became so by overeating the same foods provided to other
monkeys in the colony and avoiding physical activity.
The wider problems
of obesity This primate model also shares other physiological features
associated with human obesity, such as metabolic syndrome, characterized by an
increased resistance to insulin, which can lead to the development of type 2
diabetes and cardiovascular disease. Adipotide-treated monkeys showed marked
improvements in insulin resistance – using about 50 percent less insulin after
Arap, Pasqualini and colleagues are preparing for a clinical
trial in which obese prostate cancer patients would receive daily injections of
Adipotide for 28 consecutive days. “The question is, will their prostate cancer
become better if we can reduce their body weight and the associated health
risks,” Arap said.
Some prostate cancer treatments, such as hormone
therapy, cause weight gain. Greater weight can lead to arthritis, which in turn
causes inactivity that leads to more weight gain, a cascade effect of
co-morbidities, Arap said. Fat cells also secrete growth hormones that cancer
cells thrive upon.
Overall and abdominal body fat levels drop, with
reversible renal side effects Weight, BMI and abdominal circumference all
continued to drop for three weeks after treatment ended before slowly beginning
to reverse during the fourth week of the follow-up period.
Resonance Imaging (MRI) was used to gauge abdominal body fat, thought to be the
most dangerous area for humans to gain weight in terms of raising disease risk.
Treated monkeys’ abdominal fat levels fell by 27 percent during the study. Fat
levels increased slightly in the control group.
Lean monkeys did not lose
weight in a separate study to test for potential effects of the drug in
non-obese animals, indicating that the drug’s effect may be selective for obese
Monkeys in the studies remained bright and alert throughout,
interacting with caretakers and demonstrating no signs of nausea or food
avoidance. This is a potentially important finding since unpleasant side-effects
have limited the use of approved drugs that reduce fat absorption in the
The principal side effects were noted in the kidneys. “The
renal effect was dose-dependent, predictable and reversible,” Barnhart
Second drug developed via vascular ZIP codes This study is the
second drug developed using a vascular mapping technique created by the
Arap-Pasqualini lab. Blood vessels, they found, are more than a uniform and
ubiquitous “pipeline” that serves the circulatory system, but differ depending
on the organ or tissue that they support.
They have developed a way of
screening peptides – small bits of proteins – to identify those that bind to
specific vascular cells among the many possible “ZIP codes” present in a human
vascular map. For blood vessels that support fat cells, the target protein is
prohibitin, which they found in unusual abundance on the blood vessel cell
“The same delivery system used in mice and monkeys was recently
validated in human white fat, as reported recently by our group,” Arap
An earlier drug, which uses a different molecular address to target
the blood supply of prostate cancer, has been evaluated in a first-in-man
clinical trial, just completed at MD Anderson.
MD Anderson and some of
its researchers, including Arap and Pasqualini, have equity positions in
drug-development companies Alvos Therapeutics and Ablaris Therapeutics, which
are subjected to certain restrictions under institutional policy. MD Anderson
manages and monitors the terms of these arrangements in accordance with its
conflict-of-interest policy. This article was first published at: www.newswire.com