Dual Kinase and LSD1 Inhibition in Acute Myeloid Leukemia

急性髓系白血病的双重激酶和 LSD1 抑制

• 批准号: 10716085
• 负责人: Theodore Paul Braun
• 金额: $ 48.51万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-13 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716085
• 关键词: Acute Myelocytic Leukemia; Automobile Driving; Binding; Cell Cycle; Cell Death; Cell Line; Characteristics; Chromatin; Clinical; Clinical Treatment; Clinical Trials; Complex; Correlative Study; Data; Development; Disease; Drug Combinations; Drug Synergism; Drug Targeting; Enhancers; Epigenetic Process; Evaluation; FLT3 gene; FLT3 inhibitor; Gene Expression; Genes; Granulocyte Colony-Stimulating Factor Receptors; Investigation; JAK2 gene; KDM1A gene; Link; MEKs; MYC Family Protein; MYC gene; Mediating; Minority; Molecular; Mutation; Oncogenic; Outcome; Patients; Pharmaceutical Preparations; Phase Ib Trial; Phosphotransferases; Play; Refractory; Regulation; Relapse; Repression; Resistance; Role; Sampling; Signal Pathway; Signal Transduction; Stat5 protein; Testing; Therapeutic; Translating; Tyrosine Kinase Inhibitor; Work; acute myeloid leukemia cell; antileukemic activity; cancer cell; clinical translation; effective therapy; efficacy evaluation; epigenetic profiling; improved; inhibitor; inhibitor therapy; kinase inhibitor; member; molecular subtypes; mouse model; mutant; novel therapeutic intervention; participant enrollment; patient derived xenograft model; pre-clinical; preclinical efficacy; programs; promoter; response; synergism; transcription factor; treatment response

PROJECT SUMMARY/ABSTRACT Kinase inhibitor therapy has made a minimal impact on the clinical treatment of patients with Acute Myeloid Leukemia (AML). We have shown that inhibition of the epigenetic regulator lysine-specific demethylase 1 (LSD1) augments the efficacy of kinase inhibition in AML, including drugs targeting FLT3, cKIT and JAK2. This occurs via the repression of the MYC super enhancer (MYC-SE), leading to a loss of MYC gene expression and consequently decreased expression of a pro-proliferative gene expression program. However, we lack a complete mechanistic understating of how kinase plus LSD1 inhibition produces this effect, or whether the drug combination has important effects that are independent from the MYC-SE. Our long-term objective is to establish the efficacy of kinase plus LSD1 inhibition in AML, translating this concept into new effective treatment for patients with AML. The overall objective of this proposal is to: 1) define the mechanistic basis for drug responses to FLT3 plus LSD1 inhibition in FLT3-mutant AML and 2) evaluate the potential of dual MEK and LSD1 inhibition in NRAS-mutant AML. Our central hypothesis is that the suppression of MYC-target genes is an essential mechanism of kinase plus LSD1 inhibition-mediated cell death. In Aim 1, we will investigate three possible mechanisms for FLT3 plus LSD1 inhibition-induced suppression of MYC target genes: 1) Via inactivation of the MYC-SE leading to decreased MYC gene expression resulting in a loss of MYC-target gene expression, 2) Via inhibition of LSD1-dependent activation of MYC-target genes and 3) through inhibition of signaling pathways down-stream of activated FLT3, resulting in a loss of MYC binding to the promoters of target genes. We will also perform correlative studies investigating these mechanisms in AML patients enrolled in the FRIDA trial, receiving FLT3 plus LSD1-inhbitor therapy. In Aim 2, we will evaluate the efficacy and mechanism of action of MEK plus LSD1 inhibitor therapy in NRAS-mutant AML, using an integrated evaluation of chromatin and signaling pathway dynamics. We will also employ multiple mouse models of NRAS-mutant AML including a patient-derived xenograft model. At the completion of these studies, our expected outcomes are to 1) have identified how FLT3 plus LSD1 inhibition drives cell death in FLT3-mutant AML and 2) establish the preclinical efficacy of dual MEK plus LSD1 inhibition in NRAS-mutant AML. These studies will provide key pre-clinical rationale for expanding the indications for kinase plus LSD1 inhibitor to a larger proportion of patients with AML.

项目总结/摘要 激酶抑制剂治疗对急性髓系白血病患者的临床治疗影响甚微。 白血病（AML）。我们已经证明，抑制表观遗传调节因子赖氨酸特异性脱甲基酶1（LSD 1） 增强AML中激酶抑制的疗效，包括靶向FLT 3、cKIT和JAK 2的药物。发生这种情况 通过MYC超级增强子（MYC-SE）的抑制，导致MYC基因表达的丧失， 从而降低促增殖基因表达程序的表达。然而，我们缺乏一个 激酶加LSD 1抑制如何产生这种作用，或者药物是否 组合具有独立于MYC-SE的重要作用。我们的长期目标是建立 激酶加LSD 1抑制在AML中的疗效，将这一概念转化为新的有效治疗方法， AML患者。该提案的总体目标是：1）确定药物反应的机制基础 在FLT 3-突变AML中对FLT 3 + LSD 1抑制的作用，2）评价MEK和LSD 1双重抑制的潜力 NRAS突变型AML我们的中心假设是，MYC靶基因的抑制是一个必不可少的 激酶加LSD 1抑制介导的细胞死亡的机制。在目标1中，我们将研究三种可能的 FLT 3加LSD 1抑制诱导的MYC靶基因抑制的机制：1）通过灭活 MYC-SE导致MYC基因表达降低，导致MYC靶基因表达丧失，2）通过 抑制MYC靶基因的LSD 1依赖性活化，以及3）通过抑制信号传导途径 在活化的FLT 3下游，导致MYC与靶基因启动子结合的丧失。我们还将 在FRIDA试验中招募的AML患者中进行相关研究，调查这些机制，接受 FLT 3加LSD 1抑制剂治疗。在目标2中，我们将评估MEK plus的疗效和作用机制。 使用染色质和信号通路的综合评价，在NRAS突变型AML中进行LSD 1抑制剂治疗 动力学我们还将采用多种NRAS突变AML的小鼠模型，包括患者来源的AML。 异种移植模型在完成这些研究时，我们的预期结果是：1）确定FLT 3如何 加上LSD 1抑制驱动FLT 3突变AML中的细胞死亡，以及2）建立双重MEK的临床前疗效 加上NRAS突变AML中的LSD 1抑制。这些研究将为扩大 激酶加LSD 1抑制剂的适应症适用于更大比例的AML患者。