Indiana University Study Identifies New Pathway to Combat Leukemia

Indiana University School of Medicine cancer researchers have identified a potential way to use existing, accessible drugs to combat juvenile myelomonocytic leukemia (JMML) by targeting a specific inflammatory pathway. The findings, published in the journal Blood, open the door to more effective treatment options for this rare and aggressive childhood blood cancer, especially for high-risk pediatric patients who currently face limited options.

According to the National Cancer Institute, JMML accounts for about one to two cases per 1 million people. Bone marrow transplants are the most common treatment. However, certain variants cause immense inflammation, and current options are often ineffective.

In the study, scientists identified a specific set of three inflammatory proteins that not only fuel the leukemia's growth but also weaken the body's immune response by exhausting cancer-fighting T cells and expanding immune-suppressive cells. Using mouse models and human patient samples, they found that blocking this inflammatory chain reaction successfully slowed the cancer and supported the immune system.

We showed that blocking this inflammatory pathway reduced leukemia burden, restored immune function, decreased abnormal myeloid cell growth and significantly improved survival."

Santhosh K. Pasupuleti, Assistant Research Professor of Pediatrics, IU School of Medicine

The researchers also discovered that existing medications - such as Celecoxib, an FDA-approved anti-inflammatory, and Secukinumab, an anti-IL-17A antibody used to treat pediatric inflammatory diseases - could be repurposed and combined with standard cancer therapies called MEK inhibitors to form a new treatment strategy for patients with high-risk JMML.

"Because chronic inflammation and immune suppression are hallmarks of many cancers, targeting this pathway may have therapeutic potential beyond JMML, including in other leukemias and solid tumors where specific inflammation signaling contributes to disease progression," said Reuben Kapur, PhD, director of the IU School of Medicine Herman B Wells Center for Pediatric Research and co-corresponding author of the study.

Moving forward, the research team plans to run additional preclinical tests to determine exactly which cell types are most vulnerable to this inflammatory pathway and find the best combination of drugs. They also want to evaluate whether a simple blood test measuring these specific protein levels can help doctors predict which children will benefit the most from the treatment.

"The study's strong preclinical results provide a strong rationale for future translational and clinical development," Pasupuleti said.

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 Baskar Ramdas, Kanaka Sai Ram Padam, Rahul Kanumuri, Lakshmi Reddy Palam, Ramesh Kumar, Tzu-Chieh Ho, Wade Clapp, Kai Yang and Reuben Kapur are co-authors on the study. Additional authors include Alex G. Lee and Elliot Stieglitz from University California San Francisco, and Cheng-Kui Qu from Emory University School of Medicine.

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.