权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10931070
负责人：
Giulio Francesco Draetta
金额：
$ 28.65万
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：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10931070
关键词：
Acute Myelocytic Leukemia Adult Advanced Malignant Neoplasm Affect Apoptotic BCL-2 Protein BCL2 gene Biochemical Bioinformatics Biological Biological Assay Biology Biometry Bone Marrow Cells CD34 gene Cancer Center Cancer Science Cell Death Cell Fraction Cell Line Cell Respiration Cell Survival 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 Laboratories Linear Regressions Maintenance Malignant Neoplasms Maximum Tolerated Dose Measures Metabolic Methodology Methods Mitochondria Mitochondrial Proteins Modality Modeling Molecular Monitor Mus Normal Cell Oncogenic Oxidative Phosphorylation Oxygen Consumption Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phase Phase I Clinical Trials Phase I/II Clinical Trial Phenotype Phosphorylation Inhibition Population Proliferating Property Proteomics RNA Recommendation Recurrence Refractory Regression Analysis Relapse Residual state Respiration Respiratory Chain Safety Sampling Series Signal Pathway Techniques Testing Texas Therapeutic Time Toxic effect Translating Universities University of Texas M D Anderson Cancer Center Xenograft procedure acute myeloid leukemia cell arm chemotherapy co-clinical trial cohort design drug discovery experience first-in-human genetic profiling improved in vivo inhibitor leukemia leukemia initiating cell leukemic stem cell metabolic profile metabolomics molecular subtypes nano-string nanomolar nonlinear regression novel novel therapeutic intervention overexpression patient derived xenograft model 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.

项目总结/文摘