Researchers pursue alternative to GLP-1s to target obesity and reduce the risk of cancer

By Tatiana Del Valle
VCU Massey Comprehensive Cancer Center

Recently published research led by scientists at Virginia Commonwealth University's Massey Comprehensive Cancer Center found that targeting fat cells with sphingosine kinase 2 inhibitors could be a new strategy to combat obesity and lower the risk of its comorbidities like cancer.

Obesity touches countless lives across the United States and can lead to many other health complications. From August 2021-2023, the prevalence of obesity in adults in the U.S. was more than 40%. While GLP-1s have risen in popularity in recent years, these medications aren't a good fit for everyone since biology, genetics and metabolic health vary from person to person.

"GLP-1s are well established to help reduce body weight. However, they don't work for everyone. And once you stop taking it, the weight may come back," said study co-author Christopher Green, Ph.D., an assistant professor in the VCU School of Medicine and a member of the Cancer Biology research program at Massey. "So, there is a need to develop additional therapies, and we think that targeting adipocytes with sphingosine kinase 2 inhibitors could be a new strategy to treat people with obesity and affect their susceptibility to developing cancer."

How is obesity linked to cancer?

• Fat tissue produces excess amounts of estrogen. High levels of estrogen have been associated with increased risks of breast, endometrial, ovarian and some other cancers.
• People with obesity often have increased blood levels of insulin and insulin-like growth factor-1, which are both associated with increased risks of colorectal, thyroid, breast, prostate, ovarian and endometrial cancers.
• People with obesity often experience chronic inflammation, which promotes tumor growth.
• Fat cells (adipocytes) produce hormones called adipokines, which can influence cell growth.
• Obesity can also worsen aspects of cancer survivorship, such as quality of life, cancer recurrence, cancer progression, prognosis and risk of second primary cancers.

The research findings

In previous studies, Green and his research team found that whole body deletion of sphingosine kinase 2 led to protection from Western diet-induced obesity, fat accumulation in multiple adipose depots and reduced liver cancer in male mice.

After targeting SPHK2 in the adipocytes in these models during this study, they determined that there was a significant reduction in body weight, improved glucose tolerance, improved insulin sensitivity and reduced lipid accumulation in the liver.

These initial results led them to believe that targeting adipocytes specifically with SPHK2 inhibitors could be a new strategy to reduce the risk of cancers that stem from obesity.

What is sphingosine kinase 2?

• SPHK2 is an enzyme that creates sphingosine 1-phosphate, which is a bioactive molecule that has both intracellular and extracellular signaling roles.
• It has been shown to be involved in many types of cancer, particularly of the liver, and inflammation.
• In various models, SPHK2 was found to either promote or slow down tumor growth depending on the type of tissue involved.

What's next?

Moving forward, the team plans to continue to explore the role of SPHK2 in obesity and cancer, and they are hopeful more specific inhibitors will be developed that solely target SPHK2, as current inhibitors on the market have off-target effects.

"Additionally, future therapeutic strategies designed to more precisely target specific fat depots will be immensely beneficial," Green said. "By localizing treatment, these strategies can reduce obesity and its comorbidities, including cancer, while minimizing unwanted side effects."

The researchers emphasized that exciting advancements like these are made possible by the budding scientists on their team.

"Scientific progress like this is largely dependent on the next generation of inspired researchers," said study co-author Sarah Spiegel, Ph.D., professor in the VCU School of Medicine and member of the Cancer Biology research program at Massey. "By creating more opportunities for young scientists to pursue innovative ideas, we can further accelerate discoveries that improve prevention, treatment and patient outcomes for years to come."

In addition to Green and Spiegel, collaborators on the research project include lead author Ryan D.R. Brown, Ph.D., previously a postdoctoral research fellow at VCU and now an assistant professor at Keele University in the United Kingdom; Katarzyna Tyc, Ph.D., an assistant professor in the VCU School of Public Health and a faculty member of the Bioinformatics Shared Resource Core at the Massey; postdoctoral researchers Cynthia Weigel, Ph.D., and Yadu Vijayan, Ph.D.; and Christiane Carter, a senior bioinformatics analyst at Massey. The research was funded by the National Institutes of Health and the VCU Accelerate Fund.

This article was originally published on the VCU Massey Comprehensive Cancer Center website.