Researchers at the Indiana University School of Medicine Herman B Wells Center for Pediatric Research have developed a two-pronged strategy to combat acute myeloid leukemia (AML), an aggressive blood cancer that is notoriously difficult to treat. Early-phase clinical trials targeting the cancer’s survival systems produced rapid responses across a wide range of AML patients, suggesting an encouraging new way to overcome the deadly disease.
AML is caused by an abundance of abnormal, unhealthy cells in the blood and bone marrow called leukemia cells. While chemotherapy and bone marrow transplants are common treatments, there is no universal cure, and many patients experience relapse as the cancer adapts and becomes treatment resistant. According to the National Cancer Institute, the five-year survival rate for AML is only 32.9%.
In a study recently published in npj Precision Oncology, the scientists’ goal was to understand exactly how the leukemia cells survive therapy and how to stop that process from occurring.
“We found that AML cells are powered by two major survival systems,” said Santhosh K. Pasupuleti, PhD, assistant research professor of pediatrics and the study’s co-lead author. “First, they rely on strong growth signals driven by specific proteins. Second, they activate powerful ‘stress-survival’ programs that help them generate energy efficiently and protect themselves from damage caused by treatment.”
To bypass these defenses, the team combined two specific types of drugs that simultaneously shut down the growth signals and the stress-defense system. Their approach was successful in mouse models, showing that the combination therapy dramatically reduced leukemia burden and restored normal blood cell production. Early-phase clinical trials in patients with relapsed or resistant AML showed similar promising outcomes.
The team, representing the Wells Center's Hematologic Malignancies and Stem Cell Biology Program and the IU Melvin and Bren Simon Comprehensive Cancer Center, also observed that the therapy began working very quickly and appeared to target the disease at its biological core. In patients, the leukemia-driving genes showed suppression within days of starting the new treatment, suggesting the drugs directly interrupted the leukemia instead of just slowing its growth.
AML has various subtypes based on a patient’s specific genetic mutations. Surprisingly, the combination of the two drugs used in the study appeared to be effective for a broader range of AML patients than the researchers initially expected.
“The results indicate that the treatment may be effective across multiple AML subtypes because it targets shared pathways that many forms of AML depend on,” said Reuben Kapur, PhD, director of the Wells Center and co-author on the study. “That broader applicability makes the findings especially promising, as it means more patients could eventually benefit.”
H. Scott Boswell, MD, a longtime professor of medicine at IU, was instrumental in the early stages of this research. He conducted initial patient trials and formulated the core hypothesis that drove the study forward. Sadly, Boswell passed away during the review process of this work, and his fellow scientists have dedicated this study to his memory.
“Dr. Scott Boswell was a phenomenal physician scientist here at IU whose vision, dedication and passion made a lasting impact on our work and the field as a whole,” Kapur said. “It is with deep respect and gratitude that we dedicate this publication to his memory. His contributions continue to inspire us, and we hope this tribute helps highlight the legacy he leaves behind.”
The treatment has completed an early Phase I/II clinical trial designed primarily to evaluate safety and early signs of effectiveness. The team is now looking toward larger trials that will confirm the treatment’s long-term benefits, identify which patients are most likely to respond and explore if the strategy can be applied to other types of cancers.
“Ultimately, this research lays the groundwork for a new strategy in AML,” Pasupuleti said. “By attacking both systems at once, we aim to prevent the leukemia from escaping treatment and improve outcomes for patients facing this challenging disease.”
The researchers will also explore whether their combination of drugs can be implemented earlier in an AML patient’s treatment regimen or be used alongside currently available therapies. While these next steps are vital, it will likely be several years of further clinical testing before the treatment may become widely available to patients.
This research was supported by funding from the National Institutes of Health, Riley Children’s Foundation, Big Ten Cancer Research Consortium, Galloway Foundation and the Department of Veterans Affairs.
IU School of Medicine’s Sravanti Rangaraju, Justin Layer, Kanaka Sai Ram Padam, Larry D. Cripe, Hamid Sayar, Jill Weisenbach, Heiko Konig, Huda Salman, Baskar Ramdas, Lakshmi Reddy Palam, Lindsey D. Mayo, Utpal P. Davé and H. Scott Boswell are co-authors on the study. Additional authors include Katie J. Sargent from Indiana University Health, Sravanti Rangaraju from the University of Alabama Birmingham and Irum Khan from Northwestern University.
