XPO1 inhibitors Selinexor and Eltanexor in Combination with Venetoclax and Decitabine (ASTX727) in AML

XPO1 抑制剂 Selinexor 和 Eltanexor 联合 Venetoclax 和地西他滨 (ASTX727) 治疗 AML

• 批准号: 10337728
• 负责人: KEITH T FLAHERTY
• 金额: $ 12.5万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337728
• 关键词: Apoptosis; Automobile Driving; Award; BCL-2 Protein; BCL2 gene; Blast Cell; Blood; Blood - brain barrier anatomy; Cell Death; Cells; Clinic; Clinical Trials; Collaborations; Dacogen; Decitabine; Disease remission; Disease-Free Survival; Drug Combinations; Drug Interactions; Drug Targeting; Drug resistance; Exhibits; Generations; Goals; Hematopoietic stem cells; Human; Maximum Tolerated Dose; Measures; Mediating; Methylation; Mus; Mutation; NPM1 gene; Normal Cell; Nuclear Export; Patients; Pharmaceutical Preparations; Pharmacotherapy; Population; Proliferating; Proteins; Publishing; Relapse; Remission Induction; Resistance; TdT-Mediated dUTP Nick End Labeling Assay; Testing; Therapeutic; Toxic effect; base; candidate marker; cell killing; dosage; early phase clinical trial; human model; inhibitor/antagonist; leukemia; leukemia initiating cell; patient derived xenograft model; preclinical study; prevent; response biomarker; synergism

a) Project Summary Our studies have shown that the nuclear export inhibitors selinexor and eltanexor are highly active against AML cells and leukemia initiating cells (LICs) in patient-derived xenograft (PDX) models of human AML, with minimal toxicity to normal hematopoietic and progenitor cells (HSPCs) (Leukemia, 2013 and Leukemia, 2015). Thus, selinexor or eltanexor treament provides a therapeutic window for elimination of relapse-driving LICs while sparing normal cells. Our published earlier studies show that the BCL2 protein prevents XPO1 inhibitor mediated cell death, which suggests that selinexor or eltanexor will be highly synergistic and produce greater AML cell death if given in combination with a BCL2 inhibitor. Combinations of the BCL2 inhibitor venetoclax plus the methylation inhibitor decitabine (dacogen) have been shown to induce remission in AML (DiNardo CD et al. Blood 2019). Both venetoclax and selinexor or eltanxor are active against LICs as well as fast-proliferating bulk AML cells in patient-derived xenograft (PDX) models suggesting the hypothesis that selinexor or eltanexor together with venetoclax, and the decitabine equivalent ASTX727 will exhibit synergy in killing the LIC that sustain the AML cells in patients. Based on this hypothesis, we will perform preclinical studies to test the activity of selinexor or eltanexor in combination with venetoclax and dacogen against bulk AML cells and LICs in AML PDX models with NPM1 mutations. In Aim 1 we will determine the maximum tolerated dose of selinexor or eltanexor in combination with venetoclax and ASTX727 in NSG mice. In Aim2 we will compare the activity of venetoclax plus ASTX727 with the activity of all three drugs together to assess the added benefit of selinexor or eltanexor in killing AML LIC and determine disease-free survival. In Aim 3 we will assess the mechanism of drug interactions by measuring apoptosis by TUNEL assay on LICs and performing BH3 profiling of patient AML cells prior to therapy. It is becoming very clear that achieving complete cure for AML will require combination of multiple non-cross-resistant therapeutics. Thus, our goal for the UM1 award is to perform the preclinical studies to test the activity of selinexor, eltanexor, venetoclax and decitabine against AML cells and LICs to promote the prompt advancement of this multi-drug therapy into the clinic.

a）项目概要 我们的研究表明，核输出抑制剂selinexor和eltanexor具有高度活性 在患者来源的异种移植（PDX）模型中， 对正常造血和祖细胞（HSPC）的毒性极小 （白血病，2013年和白血病，2015年）。因此，赛灵克斯或依他克生治疗提供了一种有效的治疗方法。 治疗窗口，用于消除复发驱动的LIC，同时保留正常细胞。我们 早期发表的研究表明BCL 2蛋白阻止XPO 1抑制剂介导的细胞死亡， 这表明赛林克斯或依他赛将是高度协同的， 如果与BCL 2抑制剂联合给药，则会导致死亡。BCL 2抑制剂的组合 维奈托克加甲基化抑制剂地西他滨（达可根）已显示可诱导 AML缓解（DiNardo CD et al. Blood 2019）。venetoclax和selinexor或eltanxor都是 对患者来源的异种移植物（PDX）中的LIC以及快速增殖的大量AML细胞具有活性 模型表明，假设selinexor或eltanexor与venetoclax一起， 地西他滨等效物ASTX 727将在杀死维持AML细胞的LIC方面表现出协同作用 在病人身上。基于这一假设，我们将进行临床前研究，以测试 selinexor或eltanexor与venetoclax和dacogen组合对抗大量AML细胞， NPM1突变AML PDX模型中的LIC。在目标1中，我们将确定 NSG中Selinexor或Eltanexor与Venetoclax和ASTX 727联合给药的耐受剂量 小鼠在Aim 2中，我们将比较维奈托克+ASTX 727的活性与所有 三种药物一起使用，以评估selinexor或eltanexor在杀死AML LIC方面的额外获益， 决定无病生存率。在目标3中，我们将通过以下方式评估药物相互作用的机制： 通过TUNEL测定法测量LIC上的细胞凋亡并进行患者AML的BH 3谱分析 治疗前的细胞 越来越清楚的是，实现AML的完全治愈将需要结合 多种非交叉耐药疗法。因此，我们的UM1奖的目标是执行 临床前研究，以测试selinexor、eltanexor、venetoclax和地西他滨对 AML细胞和LIC，以促进这种多药治疗进入临床的迅速发展。