Researchers have found that the hypomethylating agent azacitidine plus the MEK inhibitor trametinib may be a promising new combination to treat patients with juvenile myelomonocytic leukemia (JMML), according to a preclinical study published by Pasupuleti et al in Molecular Therapy.
JMML is caused by a specific genetic mutation that results in the overactivity of the RAS/MAPK cellular pathway. There are currently limited therapies available to treat patients with JMML, and other drug treatments have been ineffective.
“The most common treatments for [patients with] JMML today are bone marrow transplants, but unfortunately, nearly 50% of those transplant recipients relapse,” explained senior study author Reuben Kapur, PhD, the Frieda and Albrecht Kipp Professor of Pediatrics and Director of the Herman B. Wells Center for Pediatric Research at the Indiana University School of Medicine, as well as Co–Leader of the Hematopoiesis and Hematologic Malignancies program at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center. “Chemotherapy and other medications have also been used, but their responses have not been great. We hypothesized that a combination of targeted medications could be a better option than what’s available, and we’re thrilled our preclinical studies have shown that to be the case,” he added.
Study Methods and Results
In the novel study, the researchers evaluated the efficacy of the combination of azacitidine and trametinib in a JMML model and found that it may have been capable of reducing some of the cancerous features of the disease. The researchers noted that the novel drug combination worked by decreasing the number of cancerous blood stem cells in the model and reducing the activity of the RAS/MAPK pathway.
“Our research findings demonstrated the combination of two drug therapies reduced the number of cancerous stem cells and enlargement of the spleen, and improved blood cell abnormalities often seen in [patients with] JMML,” explained lead study author Santhosh Kumar Pasupuleti, PhD, MSc, Assistant Research Professor of Pediatrics in the Program in Hematologic Malignancies and Stem Cell Biology at the Herman B. Wells Center for Pediatric Research at the Indiana University School of Medicine, and an associate member of Hematopoiesis & Hematologic Malignancies program at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center. “These results provide hope for improved therapeutic options for [patients with] JMML and highlight the potential of combination treatments in combating rare [pediatric] diseases.”
A clinical trial funded by the National Institutes of Health (NIH) has been recently approved to further study azacitidine and trametinib combination treatment in patients with JMML whose previous lines of therapy have failed. The clinical trial will be led by Elliot Stieglitz, MD, Associate Professor of Pediatrics at the University of California, San Francisco School of Medicine. Dr. Stieglitz recently conducted a separate clinical trial that found trametinib to be effective but not curative on its own in patients with JMML who did not respond to regular chemotherapy.
“Based on the information we learned, we will now test the combination of trametinib and azacitidine in patients with newly diagnosed JMML in the hope that the combination will be more effective than either drug alone,” said co–study author Elliot Stieglitz, MD, Associate Professor of Pediatrics at the University of California, San Francisco School of Medicine. “Importantly, certain ‘lower-risk’ [patients with] JMML in the upcoming trial will receive this combination of targeted treatments in place of more intense treatment [with] stem cell transplantation. We anticipate this [National Institutes of Health]–sponsored trial of targeted agents will decrease side effects and increase the number of patients who achieve remission compared [with] conventional treatments.”
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