A team led by UF researchers has used genome-wide CRISPR/cas9 screening to identify genes that are sensitive or resistant to etoposide, a chemotherapy drug used to treat pediatric acute myeloid leukemia, or AML. The findings could pave the way for developing new drug targets to overcome treatment resistance.
The study, led by UF Health Cancer Center member Jatinder Lamba, Ph.D., and published recently in the journal Blood Advances, identified several genes that have prognostic and therapeutic implications in AML. The team also identified several new genes that were not previously associated with etoposide resistance.
About 40% of children with AML relapse, and tumors in these patients develop resistance to chemotherapies. About 90% of patients with resistant or relapsed AML die within three years, showing the importance of understanding the molecular mechanisms involved in drug resistance and the need to develop other therapeutic strategies, the researchers said.
Prior studies have used genome-wide CRISPR screens to identify genes and pathways that are likely involved in the development and treatment response in AML. The current study advanced this work by integrating the CRISPR/cas9 technology with clinical outcomes data from patients treated in a pediatric AML clinical trial at St. Jude Children’s Research Hospital.
“We believe that by using this integrated approach, CRISPR screen with patient response, we can not only establish biomarkers of prognostic relevance, but also identify novel drug targets or drug combinations that are more efficacious,” Lamba said. “Our current work is focused on screening several AML cell lines and primary AML patient samples across more than 10 antileukemic agents, and it holds great clinical relevance in identifying drug combinations of therapeutic value.”
Lamba is a professor and the Frank A. Duckworth Eminent Scholar Chair in the department of pharmacotherapy & translational research in the College of Pharmacy. Other coauthors from the Cancer Center were Nathan Seligson, Pharm.D., assistant professor in the department of pharmacotherapy & translational research in the College of Pharmacy; Christopher Cogle, M.D., professor in the division of hematology & oncology in the department of medicine in the College of Medicine; and Christopher Vulpe, M.D., Ph.D., professor in the department of physiological sciences in the College of Veterinary Medicine. Trainees from the Lamba lab involved in the study include graduate students Nam Nguyen, Abdelrahman Elsayed and Mohammed Gbadamosi and postdoc Roya Rafiee.
The authors acknowledged funding from the University of Florida Opportunity funds and the Cancer Center, as well as NIH grant R01-CA132946 (to Lamba and Stanley Pounds, Ph.D., a faculty member at St. Jude Children’s Research Hospital).