Indiana University School of Medicine cancer researchers have uncovered details about what makes acute lymphoblastic leukemia (ALL) resistant to standard chemotherapy treatments. The findings, published in JCI Insight, provide a promising strategy to shut down cancer cells and introduce a new drug that could be a powerful way to defeat the most common type of leukemia in children.
ALL is a blood and bone marrow cancer that, according to the National Cancer Institute, accounts for 25% of all childhood cancers in the United States. Common treatment options are therapies designed to stop the growth of cancer cells. Unfortunately, some cancer cells learn how to adapt and become resistant to treatment.
“Our goal is to stop this leukemia from becoming chemo-resistant,” said Ji Zhang, PhD, associate professor of pediatrics at the IU School of Medicine and lead author of the study. “Because ALL is the most common pediatric cancer, finding a way to overcome drug resistance is an urgent need for many children and their families.”
In the study, the scientists investigated L-asparaginase, a chemotherapy designed to starve leukemia cells of a nutrient called asparagine. They examined how an enzyme called asparagine synthetase (ASNS) helps the cancer resist that therapy.
In mouse models, they blocked a cancer signaling pathway called GCN2 to see if it helped make the chemotherapy more effective. They also tested a new drug, ASX-173, in combination with the standard treatment to destroy the ASNS enzyme that keeps the cancer cells alive.
They found that blocking the GCN2 pathway was only somewhat effective on its own because some cancer cells developed a workaround. However, combining the therapy with the new drug ASX-173 was the missing piece to wipe out the resistant cancer cells. This method also did not cause prohibitive side effects.
“Our findings show that ALL patients who have experienced failed L-asparaginase treatment or relapsed after the treatment may benefit from a new combo treatment,” said Zhang, who is also a researcher at the Herman B Wells Center for Pediatric Research and the IU Melvin and Bren Simon Comprehensive Cancer Center. “In addition, combining ASX-173 with L-asparaginase can broaden the application of L-asparaginase to other cancers that express high levels of ASNS.”
Looking ahead, the researchers will work to further understand how ALL functions and continue to test new combinations that are even more effective and less toxic for young patients.
IU School of Medicine’s Rodney Claude, Sankalp Srivastava, Kirk A. Staschke, Lei Liu, Minghua Zhong, Shaoxiong Chen, Utpal P. Davé, Sandeep Batra, Yue Fang, Chi Zhang, Reuben Kapur and Ronald C. Wek are co-authors on the study. Additional co-authors include Harish Kothandaraman and Nadia A. Lanman from Purdue University; Carlos A. Mellado Fritz and Jing Fan from the University of Wisconsin-Madison; and Jiehao Zhou from Mayo Clinic Arizona.
This research was supported by funding from the National Institutes of Health and Riley Children’s Foundation.
