Targeting MicroRNAs to Eradicate Leukemia Stem Cells

靶向 MicroRNA 根除白血病干细胞

基本信息

批准号：
10677007
负责人：
YA-HUEI KUO
金额：
$ 49.56万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
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/10677007
关键词：
Acute Myelocytic Leukemia Adverse event Allogenic Apical Apoptosis Attenuated Automobile Driving BCL1 Oncogene Bone Marrow Cells Clinic Clinical Trials Correlative Study Data Disease Resistance Dose Down-Regulation Drug Kinetics Dynamin Endothelial Cells Endothelium Energy-Generating Resources Funding Future Growth Hematopoietic 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 Phase Phase I Clinical Trials Population Principal Investigator Production Proteins Rattus Reactive Oxygen Species Recommendation Refractory Refractory Disease Relapse Resistance 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 invention leukemia leukemia treatment leukemic stem cell mitochondrial membrane mitochondrial metabolism nonhuman primate novel novel therapeutic intervention pharmacodynamic model pharmacokinetics and pharmacodynamics pharmacologic phase I trial prevent protein biomarkers safety assessment self renewing cell stem cell homeostasis therapeutically effective

项目摘要

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.

项目概要白血病干细胞 (LSC) 位于急性髓系白血病 (AML) 细胞层级的顶端。这 LSC 的静止部分提供了自我更新细胞的储存库，可维持白血病生长，防止克隆精疲力竭，并且对治疗有抵抗力；因此，消除LSC是任何抗白血病治疗的“圣杯”。在之前的研究中，我们表明 miR-126 对于维持 LSC 的静态亚组分是必需的，防止克隆耗竭。我们展示了 SPRED1/miR-126 在 LSC 和 BM 中的自动调节环路内皮细胞 (EC) 聚集以增加 LSC 中的 miR-126 水平，保护它们并支持白血病的生长。我们表明，高 miR-126 水平是由于两种 LSC 自主机制所致，从而导致增强的通过 EC 供应外源 miR-126 进行内源性生产和非自主机制。为了消除 LSC 和 EC 中的 miR-126，我们设计了一种新型寡脱氧核苷酸抗 miR-126 抑制剂，称为米听。我们的数据表明，miRisten 药理学剥夺 miR-126 显着降低 LSC miR-126 的内源性产生并减少内皮 miR-126 的外源供应。最终结果 miR-126 的显着减少会损害 LSC 的稳态和活性，如连续移植实验。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 治疗可消除 miR-126 显着下调 BCL-2 并扰乱线粒体代谢，导致反应水平升高氧种类和 LSC 的凋亡。此外，miRisten 通过上调来破坏 LSC 线粒体功能动力相关蛋白 1 (DRP1)，诱导线粒体裂变，减少线粒体膜潜力，并诱导线粒体自噬标记蛋白的表达。由于以线粒体为中心的代谢是作为 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，进行后研究性新药申请 (IND) 支持药代动力学、药效学和毒理学研究，我们将通过 miRisten 的首次人体 1 期临床试验，迅速将 miRisten 从实验室转变为临床试验。复发/难治性 (r/r) AML 患者。该提案的中心假设是 miRisten 的目标是 miR- 126 依赖的 LSC 代谢脆弱性将为消除 LSC 提供新的治疗方法在反洗钱中。我们提出以下具体目标 (SA)： SA#1：确定 miRisten 诱导的机制 LSC 中线粒体代谢的脆弱性。 SA#2：进行药代动力学、药效学、功效 miRisten 的毒理学研究为人类研究的剂量和时间表选择提供信息。 SA#3：行为 MiListen 在 r/r AML 患者中的首次人体 1 期试验。该项目将把新发现转化为通过进行临床前研究，将 miR-126 推向临床，最终进行了 miRisten 的首次人体试验。