NIH R01 · 2024
Targeting Defective DNA Damage Response Pathways in IDH1/2-mutant AML
Heterozygous mutations in two key metabolic genes, isocitrate dehydrogenase-1 and -2 (IDH1/2), are present in up to 20% of newly diagnosed AML patients. IDH1/2 enzymes convert isocitrate to a-ketoglutarate (aKG) in the tricarboxylic acid (TCA) cycle. IDH1/2 mutations impart a neomorphic enzyme activity, leading to the conversion of aKG to the oncometabolite, 2-hydroxyglutarate (2HG). 2HG competitively inhibits aKG- dependent dioxygenases, which induces profound epigenetic alterations and impaired hematopoietic differentiation. IDH1/2 inhibitors are now FDA-approved for AML, although these agents typically are not curative, with complete response (CR) rates and median overall survival (OS)…
From the public funding record at NIH RePORTER. Describes the funded project, not the reviews below.