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Agios research demonstrates the effects of mutant IDH1 and IDH2 inhibitors in primary tumor models
Date:4/4/2013

ed from four patients with AML carrying the IDH2 mutation. Upon treatment with the inhibitor, differentiation of blast (leukemic) cells was observed. In a separate experiment in TF-1 cells, the inhibitor was able to restore the ability of the cells to differentiate upon stimulation with erythropoeitin. Each of these observations was correlated with dose-dependent reductions in the oncometabolite 2-HG, which is thought to block differentiation in leukemia cells harboring IDH mutations.

In the second article, "An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells," Agios researchers, Ingo K. Mellinghoff, M.D., of Memorial Sloan-Kettering Cancer Center, and colleagues from several institutions report that a selective mutant IDH1 inhibitor discovered at Agios blocked the ability of mutant IDH1 to produce 2-HG in an in vivo primary xenograft model, impairing the growth of patient-derived IDH1-mutant glioma (brain cancer) cells. Furthermore, reduction of 2-HG to near basal levels induced expression of genes involved in both astroctyic and oligodendrocyte differentiation.

These data suggest that targeted therapy with IDH mutant inhibitors could induce tumor cell differentiation and support clinical study of IDH1 and IDH2 mutant targeted agents for the treatment of AML and other cancers. Both articles were published online in the journal Science on April 4, 2013.


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