Characterizing vitamin B6 pathway dependency in acute myeloid leukemia

急性髓系白血病维生素 B6 通路依赖性的特征

• 批准号: 10567925
• 负责人: LINGBO ZHANG
• 金额: $ 43.92万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-05 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567925
• 关键词: Acute Myelocytic Leukemia; Affect; BCL1 Oncogene; Blast Cell; Blood Cells; Bone Marrow; CRISPR screen; Candidate Disease Gene; Cell Line; Cell Proliferation; Cells; Cessation of life; Combined Modality Therapy; Data; Dependence; Environmental Risk Factor; Enzymes; Exhibits; Genetic Engineering; Genomics; Goals; Growth; Hematologic Neoplasms; Hematopoietic Neoplasms; Hematopoietic stem cells; Immune; Impairment; In Vitro; Investigation; Leukemic Cell; Malignant - descriptor; Malignant Neoplasms; Medical; Metabolic; Metabolic Pathway; Metabolism; Molecular; Myelogenous; Normal Cell; Pathway interactions; Patients; Pattern; Persons; Pharmacology; Process; Production; Proliferating; Proteins; Reaction; Regulation; Research; Sampling; Specificity; Technology; Therapeutic; Therapeutic Effect; Toxic effect; Treatment Efficacy; Vitamin B6; Vitamins; Work; acute myeloid leukemia cell; acute toxicity; cancer cell; cancer therapy; chemotherapy; druggable target; extracellular; functional genomics; improved; in vivo; in vivo Model; inhibitor; innovation; leukemia; leukemia treatment; mouse model; new therapeutic target; novel; novel therapeutic intervention; older patient; patient derived xenograft model; peripheral blood; pharmacologic; rapid growth; single-cell RNA sequencing; synergism; therapeutic target; tumorigenesis

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is one of the most devastating blood cancers, and it affects around one million people and results in 147,000 deaths per year worldwide. AML is characterized by the abnormal production of myeloid lineage of blood cells and the rapid growth of leukemia blasts in bone marrow and peripheral blood. AML is a very aggressive cancer, and it progresses rapidly and AML patients become fatal within weeks to months. Currently, therapeutic options for AML are very limited. Only about 35% of AML patients under 60 years-old and 10% over 60 years-old benefit from standard chemotherapy. Thus, there is an urgent and unmet medical need to develop new therapeutic approaches particularly combination therapies with advanced efficacy and reduced toxicity for AML patients. Our long-term goals of the proposed research are to study abnormal vitamin pathways as metabolic dependencies in AML, to investigate critical regulators of vitamin pathways in supporting AML cell aberrant proliferation, and to identify druggable therapeutic targets in AML. We have recently uncovered vitamin B6 pathway as a novel dependency in AML. Based on this finding, we hypothesize that vitamin B6 pathway is a specific anti-leukemia target and has promising therapeutic potential to treat AML. To assess the hypothesis, we have identified multiple key enzymes in vitamin B6 dependent metabolic pathways essential for AML cell, but not for normal bone marrow hematopoietic stem and progenitor cell and immune cell, proliferation. Depletion of these key enzymes exhibited robust inhibition on AML proliferation. We have also validated vitamin B6 pathway as a pharmacologically actionable pathway and showed that vitamin B6 pathway inhibitors exhibit promising therapeutic efficacy in multiple genetically engineered AML models in vivo. These robust preliminary data encourage us to pursue three Specific Aims to further characterize vitamin B6 pathway: 1) to characterize both upstream and downstream regulators of vitamin B6 pathway in AML; 2) to evaluate the synergy between vitamin B6 pathway and BCL-2 in AML therapeutics to further enhance its efficacy; and 3) to perform functional genomics screens to identify vitamin B6 pathway synergistic effectors in AML. We propose to study AML from the aspect of vitamin B6 pathway and metabolic programming, a process which is novel and essential for AML cell proliferation. The proposed research will be focusing on both mechanistic understanding and therapeutic targeting of vitamin B6 pathway in association with different synergistic effectors in AML. The major goals of this proposal are to identify the unique vitamin B6 upstream regulators and downstream effectors as well as its synergistic effectors to treat AML. The proposal is significant because it will not only uncover the underlying mechanism but also pinpoint therapeutic targets to synergistically enhance the anti-leukemia effects in AML.

项目摘要/摘要 急性髓样白血病（AML）是最具破坏性的血液癌，它影响了大约100万人 全球每年147,000人死亡。 AML的特征是血液的异常产生 细胞和白血病在骨髓和外周血中的快速生长。 AML是一个非常侵略性的癌症，并且 它迅速发展，AML患者在数周到几个月内致命。目前，AML的治疗选择是 非常有限。 60岁以下的AML患者中，只有约35％的患者从标准中受益10％ 化学疗法。因此，尤其是开发新的治疗方法的紧急医疗需求 与AML患者的晚期功效和毒性降低的组合疗法。我们提议的长期目标 研究是将异常维生素途径作为AML中的代谢依赖性研究，以研究 维生素途径支持AML细胞异常增殖，并在AML中鉴定可药的治疗靶标。我们 最近已经发现了维生素B6途径是AML的一种新颖依赖性。基于这一发现，我们假设 维生素B6途径是一种特定的抗白血病靶标，具有治疗AML的有希望的治疗潜力。评估 假设，我们已经确定了维生素B6依赖性代谢途径的多种关键酶，对AML细胞必不可少 但不适合正常的骨髓造血干和祖细胞和免疫细胞，增殖。这些消耗 关键酶对AML增殖表现出强大的抑制作用。我们还将维生素B6途径验证为 药理学可作用的途径，表明维生素B6途径抑制剂表现出有希望的治疗 体内多种基因工程AML模型的功效。这些强大的初步数据鼓励我们追求三个 具体目的是进一步表征维生素B6途径：1）表征上游和下游调节剂 AML中的维生素B6途径； 2）评估AML疗法中维生素B6途径与Bcl-2之间的协同作用 进一步增强其功效； 3）执行功能基因组学筛查以识别维生素B6途径协同作用 AML的效应子。我们建议从维生素B6途径和代谢编程的方面研究AML，这是一个过程 这是新颖的，对于AML细胞增殖至关重要。拟议的研究将重点放在两种机械上 与AML中不同协同效应子相关的维生素B6途径的理解和治疗靶向。 该提案的主要目标是确定独特的维生素B6上游调节器和下游效应子作为 以及它的协同效应子来治疗AML。该提议很重要，因为它不仅会发现基础 机制但还指出了治疗靶标，以协同增强AML中的抗白血病作用。