Researchers Find Positive Correlation between MDS Biology, Ezatiostat MOA

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(ChemotherapyAdvisor) – The biology of myelodysplastic syndrome (MDS) and the molecular mechanism of action of ezatiostat are positively correlated, according to a team of researchers from several U.S.-based institutions. This conclusion is based on a paper titled “Prediction of Response to Therapy with Ezatiostat in Lower Risk Myelodysplastic Syndrome,” which was published in the Journal of Hematology & Oncology on May 6.

The investigators aimed to identify patients most likely to respond to ezatiostat prior to initiation of therapy. Citing previous studies where investigators had shown that “by using gene expression profiling and grouping by response, it is possible to construct a predictive score that indicates the likelihood that patients without deletion 5q will respond to lenalidomide,” they wrote. In these studies, the profile for response was linked to the biology of the disease.

The investigators previously conducted a Phase 1 dosing study in which 30 patients received one of two doses of ezatiostat in combination with lenalidomide; the combination was well tolerated and led to hematologic improvement. In the current study, RNA available from these 30 patients was analyzed for gene expression. Gene-marker analysis was also performed, and the selection of genes associated with the responders vs.nonresponders phenotype scored.

Following genomic analysis, the ezatiostat response profile contained two micro RNAs that regulate expression of genes implicated in MDS disease pathology, including genes within the jun-N-terminal kinase/c-Jun molecular pathway, which is known to be activated by ezatiostat.

The investigators concluded: “These genes are under-expressed in patients who respond to ezatiostat and over-expressed in patients who were nonresponders to the drug, suggesting that both the biology of the disease and the molecular mechanism of action of the drug are positively correlated,” the investigators wrote.


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