Targeting MicroRNAs to Eradicate Leukemia Stem Cells

靶向 MicroRNA 根除白血病干细胞

• 批准号: 10523007
• 负责人: YA-HUEI KUO
• 金额: $ 50.58万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523007
• 关键词: Acute Myelocytic Leukemia; Adverse event; Allogenic; Apoptosis; Attenuated; Automobile Driving; BCL2 gene; Bone Marrow; Cells; Clinic; Clinical Trials; Correlative Study; Data; Disease; Disease Resistance; Dose; Down-Regulation; Drug Kinetics; Dynamin; Endothelial Cells; Endothelium; Energy-Generating Resources; Funding; Future; Growth; Hematopoietic stem cells; Homeostasis; Human; Investigation; Investigational New Drug Application; Leukemic Cell; Maximum Tolerated Dose; Membrane Potentials; Metabolic; Metabolism; MicroRNAs; Mitochondria; Molecular; Molecular Mechanisms of Action; Mus; Output; Oxidative Phosphorylation; Patients; Pharmacodynamics; Pharmacology; Phase; Phase I Clinical Trials; Population; Principal Investigator; Production; Proteins; Rattus; Reactive Oxygen Species; Refractory; Relapse; Resistance; Safety; Schedule; Signal Transduction; Small RNA; Source; Stem cell transplant; Testing; Therapeutic; Toxicology; Translating; Transplantation; curative treatments; deprivation; design; exhaustion; experimental study; first-in-human; inhibitor; leukemia; leukemia treatment; leukemic stem cell; mitochondrial membrane; mitochondrial metabolism; nonhuman primate; novel; novel therapeutic intervention; pharmacodynamic model; pharmacokinetics and pharmacodynamics; phase I trial; prevent; protein biomarkers; self renewing cell; stem cell homeostasis; therapeutically effective

PROJECT SUMMARY Leukemia stem cells (LSCs) are at the apex of the acute myeloid leukemia (AML) cellular hierarchy. The quiescent fraction of LSCs provides a reservoir of self-renewing cells that sustain leukemia growth, prevent clonal exhaustion, and are treatment resistant; thus, eliminating LSCs is the `holy grail' of any anti-leukemia treatment. In previous studies, we showed that miR-126 is necessary to maintain a quiescent subfraction of LSCs that prevent clonal exhaustion. We demonstrated how SPRED1/miR-126 autoregulatory loop in LSCs and in BM endothelial cells (ECs) converge to increase miR-126 levels in LSCs, protect them and support leukemia growth. We showed that high miR-126 levels are due to both LSC autonomous mechanisms, resulting in enhanced endogenous production, and non-autonomous mechanisms, through exogenous miR-126 supply from ECs. To deplete miR-126 in LSCs and ECs, we designed a novel oligodeoxynucleotide anti-miR-126 inhibitor, called miRisten. Our data show that pharmacological miR-126 deprivation by miRisten significantly decreases LSC endogenous production of miR-126 and decreases the exogenous supply of endothelial miR-126. The net result is a significant decrease of miR-126 that damages the homeostasis and activity of LSCs, as demonstrated in serial transplant experiments. In addition, we now have evidence that miR-126 enhances mitochondrial metabolism (i.e., oxidative phosphorylation) and mitochondrial dynamics (i.e., mitochondrial fusion) in LSCs through SPRED1/ERK/p-BCL-2/NRF2 signaling. Accordingly, depletion of miR-126 by miRisten treatment significantly downregulates BCL-2 and disrupts mitochondrial metabolism, leading to increased levels of reactive oxygen species and apoptosis of LSCs. In addition, miRisten disrupts LSC mitochondrial function by upregulating the dynamin related protein 1 (DRP1), inducing mitochondrial fission, decreasing mitochondrial membrane potential, and inducing expression of mitophagy marker proteins. Since mitochondria-centered metabolism is the main metabolic energetic source for LSCs, we propose to dissect how miRisten exploits the mitochondrial metabolic vulnerability as a novel mechanism of action to eliminate LSCs. Furthermore, after conducting Investigational New Drug application (IND)-enabling pharmacokinetic, pharmacodynamic and toxicology studies, we will rapidly translate miRisten from bench to beside with a first-in-human phase 1 clinical trial of miRisten in patients with relapsed/refractory (r/r) AML. The central hypothesis of this proposal is that miRisten targets miR- 126-depended metabolic vulnerability of LSCs and will provide a novel therapeutic approach for LSC elimination in AML. We propose the following Specific Aims (SAs): SA#1: Determine the mechanisms of miRisten-induced mitochondrial metabolic vulnerability in LSCs. SA#2: Conduct pharmacokinetic, pharmacodynamic, efficacy and toxicology studies of miRisten to inform dose and schedule selection for human studies. SA#3: Conduct a first-in-human phase 1 trial of miRisten in patients with r/r AML. This project will translate novel discoveries on miR-126 into the clinic, by conducting preclincal studies that culminate in a first-in-human trial of miRisten.

项目摘要 白血病干细胞（LSC）位于急性髓样白血病（AML）细胞等级的顶点。这 LSC的静态分数提供了维持白血病生长的自我更新细胞的储层，防止克隆 精疲力尽，具有抗治疗性；因此，消除LSC是任何抗白血病治疗的“圣杯”。 在先前的研究中，我们表明miR-126对于维持LSC的静止亚折叠是必要的 防止克隆疲惫。我们证明了LSC和BM中的Spred1/mir-126自动调节环 内皮细胞（EC）会收敛以提高LSC中的miR-126水平，保护它们并支持白血病生长。 我们表明，高miR-126水平归因于两个LSC自主机制，导致增强 通过ECS的外源性miR-126供应，内源性生产和非自治机制。 为了消耗LSC和EC中的miR-126，我们设计了一种新型的寡脱氧核苷酸抗MIR-126抑制剂，称为 米里斯汀。我们的数据表明，米拉斯汀的药理学miR-126剥夺可显着降低LSC 内源性产生miR-126并减少内皮miR-126的外源性供应。最终结果 是miR-126的显着降低，损害了LSC的稳态和活性，如 串行移植实验。此外，我们现在有证据表明miR-126可以增强线粒体 LSC中的代谢（即氧化磷酸化）和线粒体动力学（即线粒体融合） 通过SPRED1/ERK/P-BCL-2/NRF2信号传导。因此，miristen治疗对miR-126的耗竭 显着下调BCL-2并破坏线粒体代谢，导致反应性水平增加 LSC的氧和凋亡。此外，miristen通过上调破坏LSC线粒体功能 动力蛋白相关蛋白1（DRP1），诱导线粒体裂变，降低线粒体膜 潜在的，并诱导线粒体标记蛋白的表达。由于以线粒体为中心的代谢是 LSC的主要代谢能源，我们建议剖析miristen如何利用线粒体 代谢脆弱性是消除LSC的新型作用机理。此外，进行后 研究新药应用（IND） - 增强药代动力学，药效和毒理学研究， 我们将迅速将Miristen从板凳转换为Miristen的第一阶段临床试验旁边 复发/难治（R/R）AML的患者。该提议的核心假设是miristen靶向mir- LSC的126个代谢脆弱性，将为LSC消除提供一种新型的治疗方法 在AML。我们提出以下特定目标（SAS）：SA＃1：确定miristen诱导的机制 LSC中的线粒体代谢脆弱性。 SA＃2：进行药代动力学，药效，功效 以及对米里斯汀（Miristen）的毒理学研究，以告知剂量并安排人类研究的选择。 SA＃3：行为 R/R AML患者的Miristen的第一阶段1期试验。这个项目将翻译出新颖的发现 MiR-126进入诊所，通过进行linc骨研究在Miristen的首次人类试验中达到高潮。