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

摘要 我们和其他人已经从基因和功能上表征了反复发生的躯体改变的贡献 与急性髓系白血病(AML)的发病机制有关，包括IDH1/IDH2突变。这导致了新的见解 探讨AML的发病机制，并导致IDH1/2抑制剂作为一种治疗药物的确认和验证 治疗急性髓系白血病的方法；第一个小分子IDH1(Ivosidenib)和IDH2(Enasidenib)抑制剂现已获得批准 用于复发/难治性IDH1/2突变型AML。然而，并不是所有的患者都对IDH1/2抑制和一个亚群有反应 对IDH抑制有反应的患者复发。我们将使用临床前研究和分析初级 从接受IDH1/2抑制剂治疗的患者中提取样本以描述敏感性和 对IDH抑制剂的耐药性，并测试新的联合治疗方法以增加治疗 IDH1/2-突变型AML的疗效。这将包括在基因定义的子集中进行基于机制的临床试验， 包括一项新的、基于机制的临床试验，该试验结合了Flt3和IDH1/2抑制对慢性粒细胞白血病患者的治疗 同时发生突变。项目1将与所有其他3个白血病孢子研究项目互动，并将利用 这个项目中的所有核心设施。我们的合作努力将包括对患者样本进行基因组讯问， 临床前治疗和机制研究，以及具有广泛相关科学的临床试验，旨在 提名IDH1/2突变的AML患者的最佳联合治疗方法。

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.