Obesity can act as a fuel for leukemia, according to a study led by scientists at the Indiana University School of Medicine. To help many patients facing aggressive blood cancers overcome this metabolic risk, researchers have identified a potential new treatment strategy that combines popular weight-loss drugs with anti-inflammatory drugs. The findings were recently published in the Journal of Clinical Investigation.
While obesity is known to increase the risk of certain blood cancers, researchers have been trying to determine exactly how the chronic condition changes the body to help leukemia thrive.
This study presents a fundamentally new understanding of how metabolic disease—specifically obesity—can directly influence the initiation and progression of leukemia. Rather than treating obesity as a passive risk factor, the work establishes it as an active biological driver linking metabolism, inflammation and cancer.”
Reuben Kapur, PhD, director of the IU School of Medicine Herman B Wells Center for Pediatric Research and co-first author of the study
After analyzing electronic health record data from more than 440,000 people in the UK Biobank and conducting experiments in mouse models, researchers discovered that obesity creates a state of chronic inflammation that accelerates the development of mutant blood stem cells that cause leukemia. This harmful environment is characterized by high levels of an inflammatory molecule called IL-17A and a decrease in the body’s natural GLP-1 metabolic signaling.
Notably, both pathways can be targeted with readily available drugs. In the study, the scientists tested a dual therapy approach involving antibodies against IL-17A, currently used to treat autoimmune diseases, and drugs that enhance GLP-1 signaling, which are used in many popular diabetes and weight loss drugs. They found that combining an IL-17A inhibitor with a GLP-1 drug successfully reduced the amount of leukemia and improved immune function in obese mice.
“Because these therapies are already available and have established safety profiles, our results raise the possibility that they may be used again either alone or in combination to improve outcomes for patients with high-risk myeloid leukemias,” said Santhosh K. Pasupuleti, PhD, assistant research professor of pediatrics at the IU School of Medicine and co-senior author of the study. “This strategy could help slow the progression of leukemia while simultaneously improving metabolic health and restoring antitumor immunity.”
The team expects to evaluate the new therapeutic approach in clinical studies to further determine whether combining IL-17A inhibitors with GLP-1 drugs can safely and effectively benefit patients with obesity-related leukemia. Future studies will also focus on identifying the patients most likely to benefit from this treatment and explore how it might translate to other cancers.
“The broader significance of this work extends beyond leukemia,” Kapur said. “Evidence that metabolic dysfunction can reprogram immune responses to promote cancer progression has implications for multiple malignancies and suggests that metabolic interventions could become a fundamental component of cancer prevention and treatment.”
Pasupouletti and Kapoor are investigators in the Wells Center’s Hematologic Malignancies and Stem Cell Biology Program and the IU Melvin and Bren Simon Comprehensive Cancer Center.
IU School of Medicine’s Rahul Kanumuri, Kanaka Sai Ram Padam, Baskar Ramdas, Lakshmi Reddy Palam, Ramesh Kumar and Laura Haneline are also co-authors on the study. Additional authors include Linke Li, Satoshi Koyama, Pradeep Natarajan, and Zhi Yu from the Broad Institute of Harvard and MIT. and Chiranjeevi Pasala, Gabriela Chiosis from Memorial Sloan Kettering Cancer Center.
This research was supported by funding from the National Institutes of Health, the Riley Children’s Foundation, the Ralph W. and Grace M. Showalter Research Trust, the Leukemia Research Foundation, and Alex’s Lemonade Stand Foundation.
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