Project 1: Increasing therapeutic efficacy in isocitrate dehydrongenase (IDH)–mutant acute myeloid leukemia (AML)

摘要

ABSTRACT We and others have genetically and functionally characterized the contribution of recurrent somatic alterations to acute myeloid leukemia (AML) pathogenesis, including IDH1/IDH2 mutations. This has led to novel insights into AML pathogenesis and led to the identification and validation of IDH1/2 inhibitors as a therapeutic approach in AML; the first small molecule IDH1 (ivosidenib) and IDH2 (enasidenib) inhibitors are now approved for relapsed/refractory IDH1/2 mutant AML. However, not all patients respond to IDH1/2 inhibition and a subset of patients relapse following responses to IDH inhibition. We will use preclinical studies and analysis of primary samples from patients treated with IDH1/2 inhibitors to delineate molecular predictors of sensitivity and resistance to IDH inhibitors, and to test new combination therapeutic approaches to increase therapeutic efficacy in IDH1/2-mutant AML. This will include mechanism-based clinical trials in genetically defined subsets, including a novel, mechanism-based clinical trial combining FLT3 and IDH1/2 inhibition in patients with concurrent mutations. Project 1 will interact with all 3 other Leukemia SPORE research projects and will utilize all core facilities in this program. Our collaborative efforts will include genomic interrogation of patient samples, preclinical therapeutic and mechanistic studies, and clinical trials with extensive correlative science aimed to nominate the best combination therapeutic approaches for AML patients with IDH1/2 mutations.