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）处于急性髓性白血病（AML）细胞层级的顶端。的 LSC的静止部分提供了自我更新细胞的储存库，其维持白血病生长，防止克隆形成， 因此，消除LSC是任何抗白血病治疗的“圣杯”。 在以前的研究中，我们发现miR-126对于维持LSC的静止亚组分是必要的， 防止克隆衰竭。我们证明了SPRED 1/miR-126自动调节环在LSC和BM中的作用， 内皮细胞（EC）聚集以增加LSC中的miR-126水平，保护它们并支持白血病生长。 我们发现高miR-126水平是由于两种LSC自主机制，导致增强的LSC表达。 内源性生产和非自主机制，通过外源性miR-126供应从EC。 为了消除LSC和EC中的miR-126，我们设计了一种新的寡脱氧核苷酸抗miR-126抑制剂， miRisten。我们的数据显示，miRisten的药理学miR-126剥夺显著降低了LSC 内源性miR-126的产生和减少内皮miR-126的外源性供应。的净结果 是miR-126的显著减少，其损害LSC的稳态和活性，如在 系列移植实验。此外，我们现在有证据表明，miR-126增强了线粒体 新陈代谢（即，氧化磷酸化）和线粒体动力学（即，线粒体融合） 通过SPRED 1/ERK/p-BCL-2/NRF 2信号转导。因此，通过miRisten处理的miR-126的消耗 显着下调BCL-2和破坏线粒体代谢，导致反应水平的增加， 氧自由基和LSC凋亡。此外，miRisten通过上调LSC的线粒体功能， 发动蛋白相关蛋白1（DRP 1），诱导线粒体分裂，减少线粒体膜 潜力，并诱导线粒体自噬标志物蛋白的表达。由于以新陈代谢为中心的新陈代谢是 LSC的主要代谢能量来源，我们建议剖析miRisten如何利用线粒体 代谢脆弱性作为消除LSC的新作用机制。此外，在进行 研究性新药申请（IND）-使药代动力学、药效学和毒理学研究成为可能， 我们将通过miRisten的首次人体1期临床试验， 复发/难治性（r/r）AML患者。该提议的中心假设是miRisten靶向miR-16。 126-LSC依赖的代谢脆弱性，并将为LSC消除提供新的治疗方法 在AML。我们提出了以下具体目标（SA）：SA #1：确定miRisten诱导的 LSC的线粒体代谢脆弱性。SA #2：进行药代动力学、药效学、疗效 miRisten的毒理学研究，为人体研究的剂量和时间表选择提供信息。SA #3：行为 miRisten在r/r AML患者中的首次人体I期试验。这个项目将把新发现翻译成 miR-126进入临床，通过进行临床前研究，最终在miRisten的首次人体试验中达到高潮。