IDH mutations in cancer and progress toward development of targeted therapeutics

Evidence is growing for the role of isocitrate dehydrogenase (IDH) mutations and D-2-hydroxyglutarate accumulation in malignancy. Preclinical studies provide proof of concept for inhibitors of mutant IDH1/2 enzymes. Early clinical data from ongoing phase I studies of mutant IDH inhibitors in patients with IDH-mutant hematologic tumors, demonstrate clinical activity with a manageable safety profile.Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes, converting isocitrate to alpha-ketoglutarate (alpha KG). IDH1 and IDH2 mutations have been identified in multiple tumor types, including gliomas and myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Here we provide an overview of the function of normal and mutated IDH, discuss the role of IDH mutations in tumorigenesis and progression and review the key clinical considerations when treating IDH-mutated tumors based on emerging clinical data from mutant IDH1/2 inhibitor trials. IDH1 and IDH2 mutations confer neomorphic activity in the mutant protein, resulting in the conversion of alpha KG to the oncometabolite, D-2-hydroxyglutarate (2-HG). The subsequent accumulation of 2-HG results in epigenetic dysregulation via inhibition of alpha KG-dependent histone and DNA demethylases, and a block in cellular differentiation. There is growing preclinical and clinical evidence suggesting that IDH mutations are involved in neoplasia. Furthermore, preclinical studies assessing small molecule inhibitors of mutant IDH1/2 enzymes have provided proof of concept that this approach decreases intracellular 2-HG levels, reverses epigenetic dysregulation and induces cellular differentiation. Phase I studies of mutant IDH inhibitors are currently ongoing in patients with IDH-mutant hematologic and solid tumors, with early data in hematologic tumors suggesting a manageable safety profile as well as clinical benefit, with a mechanism of action based on differentiation of malignant cells. Inhibition of mutant IDH shows promise as a treatment approach in hematologic malignancies, with further development ongoing in solid tumors and glioma. The mutant IDH inhibitors may have clinical utility both as single agents and in combination strategies that target additional oncogenic pathways.