Project 5: Targeting Oxidative Phosphorylation in AML

项目 5：针对 AML 中的氧化磷酸化

基本信息

批准号：
9762859
负责人：
Giulio Francesco Draetta
金额：
$ 23.62万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9762859
关键词：
Acute Myelocytic Leukemia Adult Advanced Malignant Neoplasm Affect Apoptotic BCL-2 Protein BCL2 gene Biochemical Genetics Bioinformatics Biological Biological Assay Biology Biometry Bone Marrow Cells CD34 gene Cancer Center Cancer Science Cell Death Cell Fraction Cell Line Cell Respiration Clinical Clinical Trials Complex Cytometry Data Development Disease Doctor of Medicine Dose Drug Kinetics Drug Targeting Drug usage Future Gene Expression Profile Genetic Genomics Genus Hippocampus Glycolysis Goals Growth Hematologic Neoplasms Hematopoietic stem cells Heterogeneity Human Idarubicin In Vitro Institutes Laboratories Maintenance Malignant Neoplasms Maximum Tolerated Dose Measures Metabolic Methodology Methods Mitochondria Mitochondrial Proteins Modality Modeling Molecular Monitor Mus Myeloid Leukemia Normal Cell Oncogenic Oxidative Phosphorylation Oxygen Consumption Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phase Phase I Clinical Trials Phenotype Phosphorylation Inhibition Property Proteomics RNA Recurrence Refractory Regression Analysis Relapse Residual state Respiration Respiratory Chain Safety Sampling Series Signal Pathway Structure Techniques Testing Texas Therapeutic Time Toxic effect Translating Universities University of Texas M D Anderson Cancer Center Xenograft Model Xenograft procedure acute myeloid leukemia cell arm chemotherapy cohort design drug discovery experience first-in-human genetic profiling improved in vivo inhibitor/antagonist leukemia leukemia initiating cell leukemic stem cell metabolic profile metabolomics molecular subtypes nano-string nanomolar nonlinear regression novel novel therapeutic intervention overexpression preclinical study response response biomarker stem cell population targeted treatment tumor tumor metabolism

项目摘要

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) comprises a genetically and clinically heterogeneous group of aggressive hematological malignancies. Despite advances in molecular characterization of AML, the majority of patients will relapse and die of their disease. In AML, oxidative phosphorylation (OxPhos) generates intracellular energy and metabolic intermediates necessary to promote growth and support survival. Unlike normal hematopoietic stem cells, AML and leukemia stem cells (LCS) overexpress anti- apoptotic mitochondrial protein Bcl-2, rely on OxPhos and are unable to utilize glycolysis when mitochondrial respiration is inhibited, indicating that the maintenance of mitochondrial function is essential for AML survival. We have identified a novel potent nanomolar inhibitor of OxPhos (OxPhosi) IACS-010759, selected from the series of more than 1,000 compounds across distinct structural classes. IACS-010759 has been found to inhibit complex I of OxPhos respiratory chain and block oxygen consumption. Our data demonstrated profound growth-inhibitory and pro-apoptotic effects of this agent in AML cell lines and primary AML cells at low nM concentrations, with minimal toxicity against normal BM cells. In turn, combination of OxPhos inhibitors and Bcl-2 inhibitor venetoclax is synergistic in AML. Daily dosing of IACS-010759 was well tolerated in mice, demonstrated strong efficacy in the in vivo xenograft studies utilizing the human AML patient-derived xenografts (PDX) and reduced phenotypically defined LSC fractions measured by novel technique of mass cytometry, CyTOF. Administration of OxPhosi following standard chemotherapy extended survival in primary AML PDX model. A Phase I clinical trial of IACS- 010759 in relapsed/refractory AML was recently launched at MDACC. We propose to test the hypothesis that OxPhos inhibition constitutes a novel therapeutic approach that targets a unique metabolic vulnerability of AML; and that combined blockade of mitochondrial respiration by OxPhos and Bcl-2 inhibitors will eliminate leukemia-initiating cells and produce objective responses. We will establish biomarkers of response to OxPhosi in vitro including RNA and metabolomics signatures, in a large series of primary AML with known genetic profiling, and validate these in the in vivo AML PDX models. We will further determine mechanisms of synergistic AML cell death when OxPhos inhibition is primed by Bcl-2 blockade with venetoclax, and characterize anti-AML and anti-LSC efficacy of such combination. We will further metabolically profile AML cells surviving standard chemotherapy, and test the hypothesis that OxPhosi will reduce or eliminate residual surviving AML cells. These concepts will be translated into Phase 1/2 study of standard chemotherapy and of Bcl- 2 inhibitor Venetoclax combined with IACS-010759 in patients with relapsed/refractory AML.

项目摘要/摘要急性髓样白血病（AML）包括一组遗传和临床异质的群体侵略性血液学恶性肿瘤。尽管AML的分子表征进展，但大多数患者会复发并死于疾病。在AML中，氧化磷酸化（OXPHOS）产生细胞内能量和代谢中间体，以促进生长和支持生存。与正常的造血干细胞不同，AML和白血病干细胞（LCS）过表达抗凋亡线粒体蛋白Bcl-2，依赖Oxphos，并且在线粒体呼吸受到抑制，表明线粒体功能的维持是 AML生存至关重要。我们已经确定了一种新型的Oxphos（Oxphosi）IACS-010759的有效纳摩尔抑制剂从不同的结构类别中的1,000多种化合物系列中选择。 IACS-010759 已发现可以抑制Oxphos呼吸链的复合物和氧化消耗。我们的数据在AML细胞系和原代AML细胞在低NM浓度下，对正常BM细胞的毒性最小。反过来， OXPHOS抑制剂和Bcl-2抑制剂Venetoclax的组合在AML中是协同的。每日给药 IACS-010759在小鼠中的耐受性很好，在体内异种移植研究中表现出强大的功效利用人类AML患者衍生的异种移植（PDX）并减少表型定义的LSC 通过质量细胞术的新技术测量的馏分，细胞元素。 oxphosi遵循标准化学疗法扩展生存期在原代AML PDX模型中。 IACS的I期临床试验 010759最近在MDACC启动了复发/难治性AML。我们建议检验Oxphos抑制构成一种新型治疗的假设针对AML独特代谢脆弱性的方法；那综合的封锁 OXPHOS和BCL-2抑制剂的线粒体呼吸将消除白血病发射细胞和产生客观响应。我们将在包括RNA的体外建立对Oxphosi的反应的生物标志物和代谢组学特征，在一系列具有已知基因分析的主要AML中，并验证这些在体内AML PDX模型中。我们将进一步确定协同AML细胞的机制当Oxphos抑制被VENETOCLAX阻断剂时，死亡并表征抗AML 和这种组合的抗LSC功效。我们将进一步介绍存活的AML细胞标准化学疗法，并检验了Oxphosi将减少或消除剩余存活的假设 AML细胞。这些概念将转化为标准化疗和BCL-的1/2阶段研究 2复发/难治性AML患者的IACS-010759结合IACS-010759。