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By Michele Sequeira

A Fat-Fighting Drug Discovery

UNM-led scientific team finds that their cancer-fighting compound fights obesity and diabetes, too

Eric Prossnitz, PhD, and his team hope to help 93 million obese Americans fight their fat. In a paper published in Science Translational Medicine, they reported that G-1, a cancer-fighting compound they discovered some years ago, reduces fat in obese mice. Although G-1 is currently in phase 1 clinical trials for cancer, Prossnitz and his team are planning preclinical studies to use G-1 to fight fat in obese people.

Obesity affects 40% of adults in the United States, resulting in health conditions that include heart disease, high blood pressure, type 2 diabetes and some cancers. According to the U.S. Centers for Disease Control and Prevention, obesity and its related conditions far outweigh other causes of death. Current drugs for obesity don't effectively reduce it or have undesirable side effects.

Prossnitz and his team have been studying GPER, the G protein-coupled estrogen receptor that G-1 activates, because GPER affects certain breast cancer cells. When breast cancer drugs like tamoxifen and fulvestrant block estrogen receptors in a cell's nucleus, they also activate GPER, which is found in cell membranes. Prossnitz's previous studies showed that GPER may play a role in resistance to tamoxifen and similar drugs, and that led him to wonder how G-1 affects non-cancerous cells when estrogen is lacking.

Estrogen is considered a female hormone, although men produce it at low levels. Low estrogen in women is a hallmark of menopause, and postmenopausal women also have higher rates of heart disease, high blood pressure, obesity and diabetes. So to understand whether G-1 might affect metabolism in postmenopausal women, Prossnitz and his team studied mice with low estrogen levels.

In their studies, low-estrogen female mice gained weight rapidly, even on a normal diet, and quickly became obese and diabetic. When the researchers treated these obese female mice with G-1, the mice lost weight and their diabetes went away. The researchers determined that the weight loss wasn't due to the mice eating less or moving around more; it resulted from what their bodies did with the calories they ate. Instead of storing calories as fat, the mice used them as fuel.

"Their metabolism changed," Prossnitz says. "The mice showed an increased energy expenditure."

Prossnitz's team also studied male mice, which have naturally low levels of estrogen. The male mice were fed a high-fat diet, which made them obese and diabetic, and then some were treated with G-1. Although the treated mice did not lose weight, they did not gain additional weight either, like the untreated mice. More importantly, their diabetes improved.

"This result suggests that G-1 has separate effects on obesity and diabetes," Prossnitz says. "The G-1-treated male mice were metabolically healthier, even though they were still obese."

Finally, the team also fed a high-fat diet to low-estrogen female mice. These mice became obese very quickly, but just like their sisters on a normal mouse diet, they lost weight and their diabetes improved when they were treated with G-1. These results, says Prossnitz, could point to a sex difference in the effects of the drug or in the way GPER signals in the cells of males and females.

To learn about how G-1 increases energy expenditure, the team studied brown fat cells, which generate heat instead of storing excess calories as fat. What they found surprised them: when treated with G-1, the cells expended more energy.

"This fits nicely with what we saw in mice," Prossnitz says, "and suggests that G-1 may reduce obesity by targeting brown fat cells that burn extra calories."

In a future series of experiments, Prossnitz plans to study how signals from GPER induce the cellular changes that cause more energy to be used. He hopes that one day soon G-1 could revolutionize the treatment of metabolic disorders. In the meantime, he and his team are starting the long path toward clinical trials that will test the ability G-1 to fight obesity and diabetes in people.

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"Preclinical efficacy of the GPER-selective agonist G-1 in mouse models of obesity and diabetes" was published in the January 29, 2020, issue of Science Translational Medicine. Authors are: Geetanjali Sharma, Chelin Hu, Daniela I. Staquicini, Jonathan L. Brigman, Meilian Liu, Franck Mauvais-Jarvis, Renata Pasqualini, Wadih Arap, Jeffrey B. Arterburn, Helen J. Hathaway and Eric R. Prossnitz.

Eric Prossnitz, PhD, is a Distinguished Professor and Chief of the Division of Molecular Medicine, in the Department of Internal Medicine, at The University of New Mexico School of Medicine. He co-leads the Cancer Therapeutics research program at the UNM Comprehensive Cancer Center.

UNM Comprehensive Cancer Center

The University of New Mexico Comprehensive Cancer Center is the Official Cancer Center of New Mexico and the only National Cancer Institute-designated Cancer Center in a 500-mile radius.

Its 131 board-certified oncology specialty physicians include cancer surgeons in every specialty (abdominal, thoracic, bone and soft tissue, neurosurgery, genitourinary, gynecology, and head and neck cancers), adult and pediatric hematologists/medical oncologists, gynecologic oncologists, and radiation oncologists. They, along with more than 600 other cancer healthcare professionals (nurses, pharmacists, nutritionists, navigators, psychologists and social workers), provide treatment to 65% of New Mexico’s cancer patients from all across the state and partner with community health systems statewide to provide cancer care closer to home. They treated 13,578 patients in 105,748 ambulatory clinic visits in addition to in-patient hospitalizations at UNM Hospital.

A total of 1,610 patients participated in cancer clinical trials, including 696 patients who participated in clinical trials testing new cancer treatments that include tests of novel cancer prevention strategies and cancer genome sequencing.

The 132 cancer research scientists affiliated with the UNMCCC were awarded $34.5 million in federal and private grants and contracts for cancer research projects and published 301 high quality publications. Promoting economic development, they filed more than 30 new patents since FY16, and since 2010, have launched 11 new biotechnology start-up companies. Scientists associated with the UNMCCC Cancer Control & Disparities have conducted more than 60 statewide community-based cancer education, prevention, screening, and behavioral intervention studies involving more than 10,000 New Mexicans.

Finally, the physicians, scientists and staff have provided education and training experiences to more than 230 high school, undergraduate, graduate, and postdoctoral fellowship students in cancer research and cancer health care delivery.

Categories: Comprehensive Cancer Center