Weight loss and anti inflammatory drugs combine to combat leukemia

Obesity can act as fuel for leukemia, according to a study led by Indiana University School of Medicine scientists. To help many patients facing aggressive blood cancers overcome this metabolic risk, researchers identified a potential new treatment strategy that combines popular weight-loss medications 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, the researchers sought 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 an equal 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, the researchers discovered that obesity creates a state of chronic inflammation that accelerates the growth of mutated, leukemia-causing blood stem cells. This harmful environment is marked 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 medications. In the study, the scientists tested a dual-therapy approach involving anti–IL-17A antibodies, which are currently used to treat autoimmune diseases, and drugs that boost GLP-1 signaling, which are used in several popular diabetes and weight-loss medicines. They found that combining an IL-17A blocker with a GLP-1 drug successfully lowered 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 of repurposing them 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 reduce leukemia progression while simultaneously improving metabolic health and restoring anti-tumor 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-associated leukemia. Future studies will also focus on identifying which patients are most likely to benefit from this treatment and explore how it may translate to other forms of cancer.

"The broader significance of this work extends beyond leukemia," Kapur said. "The demonstration that metabolic dysfunction can reprogram immune responses to promote cancer progression has implications for multiple malignancies and suggests that metabolic interventions could become a foundational component of cancer prevention and therapy."

Pasupuleti and Kapur are researchers 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 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, Ralph W. and Grace M. Showalter Research Trust, Leukemia Research Foundation and Alex's Lemonade Stand Foundation.