Mount Sinai Scientists Show That a Novel Therapy Could Be Effective Against Pediatric Leukemia
Therapy could also fight pancreatic and other cancers, researchers say
- Thousands of individuals with the condition are likely undiagnosed.
- Study identifies underutilization of genetic testing as a major contributor to missed diagnoses.
- Findings underscore the growing importance of genetic testing as precision therapies advance toward patients.
Mount Sinai researchers have developed a therapy that shows promise against a deadly pediatric leukemia. The small-molecule therapy was highly effective in fighting a type of acute myeloid leukemia in both in vitro and in vivo experiments, according to research published in Science Translational Medicine in September.
The therapy, named MS67, causes the degradation of the WDR5 protein, which drives the proliferation of acute myeloid leukemia with a specific genetic makeup called mixed lineage leukemia rearrangement. This type of leukemia is more common in children, has very poor response to standard treatments and a dismal prognosis, and until now has confounded researchers.
WDR5 also plays an important role in driving the proliferation of other cancers such as pancreatic cancer, so researchers believe that it is likely that WDR5 small-molecule degraders such as MS67 could also be effective in treating those cancers.
“This study is the first to demonstrate that pharmacological degradation of WDR5, which selectively eliminates the proten, is an effective and superior therapeutic strategy than pharmacological inhibition, or blocking, of WDR5 for the treatment of WDR5-dependent cancers including acute myeloid leukemia with mixed lineage leukemia rearrangement,” said Jian Jin, PhD, the Mount Sinai Professor in Therapeutics Discovery and Director of the Mount Sinai Center for Therapeutics Discovery at the Icahn School of Medicine at Mount Sinai. “In addition, MS67 is the first WDR5 small-molecule degrader that exhibits robust anti-tumor activities in vivo.”
The research team led by Dr. Jin; Greg Wang, PhD, of the University of North Carolina at Chapel Hill; and Aneel Aggarwal, PhD, Professor of Pharmacological Sciences, and Oncological Sciences, at The Tisch Cancer Institute at Mount Sinai, discovered MS67, a novel, highly potent and selective small-molecule degrader of WDR5, which effectively suppressed the growth of this type of acute myeloid leukemia cells derived from patients both in vitro and in vivo, using patient cancer cells in mouse models. Using a battery of biochemical, biophysical, structural, cellular, genomic, and in vivo studies, the research team demonstrated that MS67 is a much superior therapeutic agent than other therapies that inhibit instead of degrade WDR5.
This research was supported in part by the grants R01GM122749, P30CA196521, R01CA211336, R01CA215284, and R35GM131780 from the U.S. National Institutes of Health.
About the Mount Sinai Health System
Mount Sinai Health System is one of the nation’s leading integrated academic health systems and one of the largest in the New York metropolitan area. Its comprehensive system includes seven hospitals, more than 400 outpatient practices, over 600 research and clinical laboratories, the Icahn School of Medicine at Mount Sinai, the Graduate School of Biomedical Sciences, and the Mount Sinai Phillips School of Nursing. Together, the Health System comprises approximately 48,000 employees, more than 9,000 physicians, and 8,600 nurses.
As a leading learning health system, Mount Sinai combines clinical expertise with scientific discovery to improve patient care while training the next generation of health care and biomedical leaders. The Health System provides care across every stage of life, from prenatal care through geriatrics, while advancing personalized medicine through artificial intelligence, data science, and biomedical research.
Mount Sinai is consistently recognized among the nation’s leading academic health systems for patient care, research, and education. The Mount Sinai Hospital is ranked No. 1 in New York by Newsweek and No. 5 on the magazine’s World’s Best Hospitals list. The Icahn School of Medicine at Mount Sinai ranks No. 11 among U.S. medical schools and No. 1 among freestanding medical schools for National Institutes of Health funding, reflecting the strength of its scientific enterprise and leadership in biomedical research.