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

A)项目摘要 我们的研究表明，核出口抑制剂Selinexor和Eltanexor具有很高的活性 在患者来源的异种移植(PDX)模型中抗AML细胞和白血病起始细胞(LICs) 对正常造血祖细胞(HSPC)毒性最小 (白血病，2013和白血病，2015)。因此，Selinexor或eltanexor治疗提供了一种 在保留正常细胞的同时，消除复发驱动的LIC的治疗窗口。我们的 早些时候发表的研究表明，BCL2蛋白可以防止XPO1抑制剂介导的细胞死亡， 这表明Selinexor或Eltanexor将具有高度的协同作用，并产生更多的AML细胞 如果与bcl2抑制剂联合使用，则会导致死亡。BCL2抑制剂的组合 文奈德加甲基化抑制剂地西他滨(达克因)已被证明能诱导 急性髓系白血病的缓解(DiNardo CD等人血液2019)。Ventoclax和Selinexor或eltanxor都是 在患者来源的异种移植(PDX)中对LICs和快速增殖的大量AML细胞的活性 模型表明Selinexor或Eltanexor与ventoclax一起的假设，以及 地西他滨类似物ASTX727将在杀伤维持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联合万乃馨和达康对AML细胞的杀伤作用 具有NPM1突变的AML PDX模型中的LICs。在目标1中，我们将确定最大 NSG耐受量Selinexor或Eltanexor与万乃馨和ASTX727的联合应用 老鼠。在AIM2中，我们将比较VENTOTOCLAX+ASTX727和ALL的活性 三种药物一起评估Selinexor或Eltanexor在杀死AML LIC和AML方面的额外好处 确定无病存活率。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 原位末端标记法检测急性髓系白血病患者LIC细胞凋亡率及BH3谱分析 治疗前的细胞数量。 越来越清楚的是，要完全治愈AML将需要结合以下几项 多种非交叉耐药疗法。因此，我们的UM1奖项的目标是执行 Selinexor、Eltanexor、Venotclax和Decitabine抗肿瘤活性的临床前研究 AML细胞和LICs，以促进这一多药疗法迅速进入临床。

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.