Movie/image: Influence of the cellular enzyme SAMHD1 on the antitumour effect of cytarabine (Ara-C) in acute myeloid leukaemia (AML) – cell line THP-1. Copyright Cinatl et al.
Until now, it has been impossible to predict which patients suffering from acute myeloid leukaemia (AML) will respond to standard cytarabine-based chemotherapy – and which will not. Therefore, all patients receive the same therapy, although only some will benefit from the treatment, which is associated with considerable side effects. Researchers from the Frankfurt Foundation for Children with Cancer and Goethe University have now discovered a new biomarker that can be used to identify patients who will respond to the therapy with a high degree of accuracy. In addition, the results open up new possibilities for treating leukaemia patients for whom no suitable therapy is currently available.
The active substance cytarabine forms the backbone of chemotherapies for the treatment of AML. In cancer cells, cytarabine is activated by the binding of phosphate groups. In his research group, funded by the Frankfurt Foundation for Children with Cancer, Prof. Jindrich Cinatl examined cytarabine-resistant AML cells from the Resistant Cancer Cell Line (RCCL) collection (www.kent.ac.uk/stms/cmp/RCCL/RCCLabout.html), which he runs together with Prof. Martin Michaelis (University of Kent, Canterbury, UK). Prof. Cinatl discovered that the toxicity of cytarabine to AML cells correlates with the concentration of the cellular enzyme SAMHD1, which makes it possible to predict the sensitivity of AML cells to cytarabine.
Based on this initial finding, a consortium led by Prof. Cinatl together with Prof. Oliver Keppler (who moved from the Institute of Medical Virology at Goethe University to Ludwig-Maximilians-Universität Munich during the study) subsequently showed that the enzyme SAMHD1 cleaves phosphate groups from the activated form of cytarabine and converts cytarabine back to its inactive form.
In a collaboration with clinicians (led by Prof. Hubert Serve, Medical Clinic II, Goethe University), it was shown that the SAMHD1 concentrations found in leukaemia cells also enabled AML patients who benefit from cytarabine-based chemotherapies to be identified clinically with high accuracy. This makes SAMHD1 a new clinical biomarker that allows cytarabine-based therapies to be targeted to AML patients who are highly likely to respond to the treatment and to spare patients who are highly unlikely to respond the toxic side effects. In addition, the group led by Frankfurt researchers showed that inhibiting SAMHD1 sensitises AML cells to cytarabine, opening up new treatment options for leukaemia patients for whom there are currently no effective treatments.
The results were published in the scientific journal Nature Medicine and can be found at the following web address:
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