Mystery of anticancer drug nelarabine for leukaemia treatment solved
Acute lymphoblastic leukaemia (ALL) is the most common cancer in children. With the active substance nelarabine, T-ALL, a subtype that resembles T-lymphocytes, can be treated well. However, B-ALL, a subtype that resembles B lymphocytes, cannot. The reason for this difference has been a mystery to oncologists since the 1980s. An international research team led by Goethe University and the University of Kent has now found the reason: B-ALL cells contain the enzyme SAMHD1, which inactivates the drug.
In the current issue of Communications Biology, Prof. Jindrich Cinatl from the Institute of Medical Virology at Goethe University and Prof. Martin Michaelis from the School of Biosciences at the University of Kent report on their investigations with neralabine on various cell lines. “Nelarabine is a precursor of the drug, a prodrug that only becomes effective when it is linked to three phosphate groups in the leukaemia cell,” explains Prof. Cinatl. “In studies of different ALL cell lines and leukaemia cells from ALL patients, we have now been able to show that the enzyme SAMHD1 cleaves the phosphate groups again, so that the drug loses its effect.” Because B-ALL cells contain more SAMHD1 than T-ALL cells, nelarabine is less effective in B- ALL.
These results may improve the therapy of ALL in the future. In rare cases, B-ALL cells contain only little SAMHD1, so that nelarabine could be used here. Conversely, there are also rare cases of T-ALL that have a lot of SAMHD1. In such cases, the otherwise effective nelarabine would not be a suitable drug. Prof. Michaelis says: “SAMHD1 is therefore a biomarker that allows us to better adapt the treatment with nelarabine to the individual situation of the ALL patient.”
Tamara Rothenburger, whose doctoral thesis was funded by the association “Hilfe für krebskranke Kinder Frankfurt Frankfurt e.V.”, looks back on her research with satisfaction: “I hope that many children suffering from leukaemia will benefit from the results.” The research was also supported by the Frankfurt Foundation for Children with Cancer. Other members of the research group were Ludwig-Maximilians-Universität Munich and University College London.
Publication: Tamara Rothenburger, Katie-May McLaughlin, Tobias Herold, Constanze Schneider, Thomas Oellerich, Florian Rothweiler, Andrew Feber, Tim R. Fenton, Mark N. Wass, Oliver T. Keppler, Martin Michaelis, Jindrich Cinatl . SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine. Communications Biology, DOI 10.1038/s42003-020-1052-8 https://rdcu.be/b49lf
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