Drug mimics beneficial effects of fasting in mice
Blocking arginine metabolism leads to improved metabolic health, weight
loss

Date:
January 20, 2022
Source:
Washington University School of Medicine
Summary:
An investigational cancer drug that starves tumors of their energy
supply also shows evidence of improving whole body metabolism,
leading to improved weight control, according to a new study
in mice.



FULL STORY ==========================================================================
An investigational cancer drug that starves tumors of their energy
supply also shows evidence of improving whole body metabolism, leading to improved weight control, according to a new study in mice from researchers
at Washington University School of Medicine in St. Louis.


==========================================================================
The findings are published in the journal Cell Reports Medicine.

In a group of mice genetically prone to obesity and in a separate group of
mice that became obese due to a high-fat, high-sugar diet, treatment with
the drug ADI-PEG 20 increased insulin sensitivity, improved cholesterol
levels, reduced fat buildup in the liver and lowered inflammation. For
the mice genetically prone to obesity from birth, treatment with the
drug protected them from their typical weight gain. And for the mice
that became obese on a high-fat, high- sugar diet, treatment with the
drug caused the mice to lose weight.

The drug is being investigated for potential use as a treatment for a
number of cancers, including sarcoma, breast and pancreatic cancers. The
drug breaks down the amino acid arginine in the blood, which deprives
cancer cells of a key source of fuel. The researchers became interested
in studying the drug after finding that genes responsible for breaking
down arginine are dialed up tremendously when the body is in a fasting
state. They wondered if the drug could mimic this effect of fasting.

Indeed, the researchers found that the drug triggers cells to undergo a
process called autophagy, or self-eating, a cellular-level housecleaning process. Cells undergoing autophagy burn their own cellular waste products
for fuel. During fasting, when no new fuel is coming from the outside,
cells shift to autophagy, turning inward for their fuel supply.

"Giving this drug seems to mimic some of the metabolic and therapeutic
effects of fasting," said senior author Brian DeBosch, MD, PhD, an
associate professor of pediatrics. "I was surprised by how large the
effect was. In the mice prone to weight gain, the group that received the
drug ended up weighing about 25% less than the mice that didn't get the
drug. And in the mice on the high-fat, high-sugar diet, we saw similar
weight loss from the drug. Also, we don't think that the preponderance
of the drug's metabolic benefits are from changes in body weight. In
fact, for several outcome measures, the metabolic changes preceded
significant changes in weight." The drug has been tested in clinical
trials investigating its safety and efficacy in treating several tumor
types, including breast, prostate, pancreatic and liver cancers. In
general, metabolic therapies tend to have fewer side effects and are
safer than chemotherapy, radiation and even newer immunotherapies used
to treat cancer.

DeBosch, a pediatric gastroenterologist who treats patients at St. Louis Children's Hospital, said the research team would like to conduct a
clinical trial of the drug to see if it triggers similar metabolic
benefits and weight loss in people who are overweight or obese. One
question that remains is whether the drug is safe to take long term. It's
not a small molecule, like a statin, that can be taken for decades. The
drug is a protein, so there is a possibility that patients could develop
an immune response to it over time.

However, DeBosch still sees a potential role for such a treatment over
a matter of weeks to months.

"Many patients with obesity who are considering bariatric surgery must
first lose some weight to make the procedure safer," DeBosch said. "It
can be difficult for such patients to lose up to 10% of their body
weight before the surgery. This type of therapy could potentially serve
as a bridge to help patients lose weight before bariatric surgery,
to reduce the risk of complications during and after the procedure."
This work was supported by the National Institutes of Health (NIH),
grant numbers 1R01DK126622-01A1, 1R01HL147968-01A1, 1R21AT010520-01, UL1TR002345 and R56 DK115764; a Pilot Research Award from the
American Association for the Study of Liver Disease; an AGA-Gilead
Sciences Research Scholar Award in Liver Disease; the AGA-Allergan
Foundation Pilot Research Award in Non-Alcoholic Fatty Liver Disease;
the Washington University Digestive Disease Research Core Center, grant
number P30DK52574; the Washington University Diabetes Research Center,
grant number P30DK020579; the Nutrition & Obesity Research Center, grant
number P30DK056341; the Association for Aging Research Junior Faculty
Award; the Robert Wood Johnson Foundation; the Washington University
Center for Autophagy Therapeutics Research; the Longer Life Foundation;
and a Washington University School of Medicine Pediatric Gastroenterology Research Training Grant, number T32DK077653.

========================================================================== Story Source: Materials provided by
Washington_University_School_of_Medicine. Original written by Julia
Evangelou Strait. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Yiming Zhang, Cassandra B. Higgins, Brian A. Van Tine, John
S. Bomalaski,
Brian J. DeBosch. Pegylated arginine deiminase drives
arginine turnover and systemic autophagy to dictate energy
metabolism. Cell Reports Medicine, 2022; 3 (1): 100498 DOI:
10.1016/j.xcrm.2021.100498 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220120125413.htm

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