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

项目1：提高异柠檬酸脱氢酶（IDH）突变型急性髓系白血病（AML）的治疗效果

• 批准号: 10474275
• 负责人: Ross L Levine
• 金额: $ 36.77万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-24 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10474275
• 关键词: Acute Myelocytic Leukemia; Alleles; Biological Assay; Chemotherapy-Oncologic Procedure; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Core Facility; Coupled; Development; Disease; Dose; Enrollment; FLT3 gene; FLT3 inhibitor; Genes; Genetic study; Genomics; Genotype; Goals; In complete remission; Investigation; Isocitrates; Lead; Memorial Sloan-Kettering Cancer Center; Modeling; Molecular; Mutate; Mutation; Pathogenesis; Pathway interactions; Patients; Recurrence; Refractory; Relapse; Research Project Grants; Resistance; Role; Sampling; Science; Signal Transduction; Testing; Therapeutic; Therapeutic Trials; Treatment Efficacy; Validation; base; improved outcome; inhibitor; inhibitor therapy; insight; leukemia; mouse model; mutant; novel; novel therapeutic intervention; novel therapeutics; patient subsets; pre-clinical; preclinical study; prevent; programs; relapse patients; resistance mechanism; response; small molecule; targeted treatment; therapy resistant

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.

摘要 我们和其他人已经从遗传和功能上描述了周期性体细胞改变的作用 急性髓性白血病（AML）发病机制，包括IDH 1/IDH 2突变。这导致了新的见解 AML发病机制，并导致IDH 1/2抑制剂作为治疗药物的鉴定和验证 第一个小分子IDH 1（ivosidenib）和IDH 2（enasidenib）抑制剂现已获批 复发性/难治性IDH 1/2突变型AML。然而，并非所有患者都对IDH 1/2抑制有反应， 的患者在对IDH抑制反应后复发。我们将使用临床前研究和分析的主要 从接受IDH 1/2抑制剂治疗的患者中采集样本，以描述敏感性的分子预测因子， IDH抑制剂的耐药性，并测试新的组合治疗方法，以增加治疗 IDH 1/2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，在患有以下疾病的患者中联合FLT 3和IDH 1/2抑制 并发突变项目1将与所有其他3个白血病孢子研究项目互动，并将利用 这个项目的所有核心设施。我们的合作将包括对患者样本进行基因组分析， 临床前治疗和机制研究，以及广泛相关科学的临床试验，旨在 提名IDH 1/2突变AML患者的最佳联合治疗方法。