ABSTRACT
Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are frequently found in several human cancer types including acute myeloid leukemia (AML) and lead to the production of high levels of the oncometabolite (R)-2-hydroxyglutarate (R-2HG). Here we report the characterization of BAY1436032, a novel pan-mutant IDH1 inhibitor, both in vitro and in vivo. BAY1436032 specifically inhibits R-2HG production and colony growth, and induces myeloid differentiation of AML cells carrying IDH1R132H, IDH1R132C, IDH1R132G, IDH1R132L and IDH1R132S mutations. In addition, the compound impacts on DNA methylation and attenuates histone hypermethylation. Oral administration of BAY1436032 led to leukemic blast clearance, myeloid differentiation, depletion of leukemic stem cells and prolonged survival in two independent patient-derived xenograft IDH1 mutant AML mouse models. Together, BAY1436032 is highly effective against all major types of IDH1 mutant AML.
Subject(s)
Aniline Compounds/therapeutic use , Antineoplastic Agents/therapeutic use , Benzimidazoles/therapeutic use , Enzyme Inhibitors/therapeutic use , Isocitrate Dehydrogenase/antagonists & inhibitors , Leukemia, Myeloid, Acute/drug therapy , Neoplasm Proteins/antagonists & inhibitors , Aniline Compounds/pharmacology , Animals , Antineoplastic Agents/pharmacology , Benzimidazoles/pharmacology , Cell Line, Tumor , DNA Methylation/drug effects , Enzyme Inhibitors/pharmacology , Glutarates/metabolism , Histone Code/drug effects , Humans , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/genetics , Methylation/drug effects , Mice , Molecular Targeted Therapy , Mutation , Mutation, Missense , Myeloid Cells/drug effects , Myelopoiesis/drug effects , Neoplasm Proteins/genetics , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/enzymology , Point Mutation , Protein Processing, Post-Translational/drug effects , Tumor Stem Cell Assay , Xenograft Model Antitumor AssaysABSTRACT
We evaluated a worksite smoking cessation program that employed multicomponents including support groups, incentives, and competition. The combination of incentives and other components increased participation rates to over 80%. Forty-two percent of smokers were abstinent at six months, compared to 13 percent of a control group (difference 29 percent, 95% CI 9, 49).
