Therapeutic targeting of glutamine metabolism in MDS

MDS 中谷氨酰胺代谢的治疗靶向

• 批准号: 9901359
• 负责人: Marina Y Konopleva
• 金额: $ 48.15万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901359
• 关键词: AML/MDS; Acute Myelocytic Leukemia; Address; Affect; Aftercare; Amino Acids; Apoptosis; Azacitidine; Bioavailable; Biochemical; Bioenergetics; Biological Assay; Biological Markers; Bone Marrow; Bone Marrow Cells; Carbon; Cell Line; Cell Proliferation; Cell Respiration; Cell Survival; Cells; Cellular Metabolic Process; Citric Acid Cycle; Clinical; Clinical Trials; Coculture Techniques; Combined Modality Therapy; Complex; Cultured Cells; Cytogenetics; DNA; DNA Methylation; Data; Dependence; Disease; Dose; Dysmyelopoietic Syndromes; Elderly; Enzymes; Essential Amino Acids; Exposure to; Extramedullary; Gene Silencing; Generations; Genetic Engineering; Genetic Transcription; Glutamates; Glutaminase; Glutamine; Glutathione; Glycolysis; Growth; Hematologic Neoplasms; Homeostasis; Human; Hypermethylation; Hypoxia; In Vitro; Leukemic Cell; Malignant Neoplasms; Mesenchymal; Mesenchymal Stem Cells; Metabolic; Metabolic Pathway; Metabolism; Methylation; Mitochondria; Modeling; Molecular; Monitor; Mus; Oral; Output; Oxidation-Reduction; Pancytopenia; Patients; Pattern; Phase; Phase I/II Clinical Trial; Phase I/II Trial; Play; Process; Production; Proliferating; Public Health; Reaction; Recurrence; Recurrent disease; Refractory Disease; Respiration; Role; Series; Signal Transduction Pathway; Source; Stress; Testing; Tetanus Helper Peptide; Therapeutic; Transgenic Organisms; Treatment Efficacy; Treatment Failure; Validation; Work; Xenograft procedure; acute myeloid leukemia cell; base; cancer cell; carbon skeleton; cell growth; combat; design; effective therapy; epigenetic regulation; first-in-human; genome-wide; high risk; in vivo; inhibitor/antagonist; leukemia; mRNA Expression; metabolic profile; metabolomics; methylome; mouse model; neoplastic cell; new therapeutic target; novel; outcome forecast; overexpression; pharmacodynamic biomarker; pre-clinical; preclinical efficacy; public health relevance; response; small hairpin RNA; small molecule inhibitor; stem; stem cells; therapeutic evaluation; therapeutic target; tumor; tumor microenvironment

 DESCRIPTION (provided by applicant): Metabolic reprogramming by cancer cells is critical to facilitate their proliferation and survival against micro environmental stresses. Glutamine (Gln) i an essential amino acid that plays a unique role in the metabolism of proliferating cancer cells, providing building blocks to sustain cell proliferation and regulating redox homeostasis and signal transduction pathways. Glutaminase (GLS) is an enzyme that initiates this process by converting glutamine to glutamate which is subsequently used in multiple reactions that support tumor cell growth and survival, including the generation of energy (TCA cycle), synthesis of amino acids and production of glutathione. Importantly, it has also been shown that GLS inhibition can reduce 2HG levels in tumors thus increasing TET activity and leading to decreased methylation. Recent findings from our group and others indicate that AML cells depend on Gln as a major carbon source for growth and survival. Inhibition of glutaminase with novel selective small molecule inhibitor CB-839, or silencing GLS expression with inducible shRNA inhibited mitochondrial respiration, reduced cell growth and induced apoptosis in a subset of leukemia cell lines and primary AML cells. Further, co-culture of leukemia cells with bone marrow-derived mesenchymal stem cells caused metabolic reprogramming in both, stroma and cancer, whereby glycolytic stroma supported oxidative metabolism of leukemic cells, in part by supplying glutamine. Myelodysplastic syndromes (MDS) are incurable malignancies that need newer therapeutic targets. Our preliminary data demonstrate that GLS is overexpressed in AML with complex cytogenetics, in high risk MDS stem cells and is associated with worse prognosis in MDS patients. We hypothesize that the glutaminase is a therapeutic target in MDS and metabolic reprogramming involved in transformation of MDS into AML. We propose to monitor the changes in metabolism in the conversion of MDS to AML in mouse models and determine if inhibiting glutaminolysis inhibits progression. This project will (1) characterize glutamine-dependent MDS subtypes; (2) determine mechanisms and investigate pre-clinical efficacy of the novel, potent, orally bioavailable GLS inhibitor CB-839 in MDS models; and (3) test therapeutic efficacy of CB-839 combined with 5-azacytidine in a Phase I/II clinical trial in patients with intermediate and high-risk MDS. We will specifically determine the efficacy of this combination in eliminating MDS stem cells, and analyze the effects on their methylation states. Since hypermethylation of DNA is an important hallmark of MDS, a combination of two hypomethylating approaches (via distinct mechanisms of action) will be potentially efficacious in MDS. The proposed work will generate a better understanding of the metabolic pathways in MDS.

 描述（由申请人提供）：癌细胞的代谢重编程对于促进其增殖和抵抗微环境压力的生存至关重要。谷氨酰胺（Gln）是一种必需氨基酸，在增殖的癌细胞的代谢中发挥着独特的作用，为癌细胞提供了基础。维持细胞增殖并调节氧化还原稳态和信号转导途径，谷氨酰胺酶 (GLS) 是一种通过将谷氨酰胺转化为谷氨酸来启动这一过程的酶，谷氨酸随后用于多种用途。支持肿瘤细胞生长和存活的反应，包括能量的产生（TCA 循环）、氨基酸的合成和谷胱甘肽的产生。重要的是，GLS 抑制可以降低肿瘤中的 2HG 水平，从而增加 TET 活性并导致。我们小组和其他人的最新研究结果表明，AML 细胞依赖谷氨酰胺作为生长和存活的主要碳源，用新型选择性小分子抑制剂 CB-839 或用诱导型 shRNA 沉默 GLS 表达可抑制白血病细胞系和原代 AML 细胞中的线粒体呼吸，减少细胞生长并诱导细胞凋亡。此外，白血病细胞与骨髓来源的间充质干细胞的共培养会导致两者的代谢重编程。基质和癌症是无法治愈的，其中糖酵解基质部分通过提供谷氨酰胺来支持白血病细胞的氧化代谢。我们的初步数据表明，GLS 在具有复杂细胞遗传学的 AML 和高风险 MDS 干细胞中过度表达，并且与 MDS 患者的较差预后相关，我们发现谷氨酰胺酶是 MDS 和代谢的治疗靶点。我们建议在小鼠模型中监测 MDS 转化为 AML 过程中的代谢变化，并确定抑制谷氨酰胺分解是否会抑制进展。 (1) 表征谷氨酰胺依赖性 MDS 亚型；(2) 确定新型、有效、口服生物可利用的 GLS 抑制剂 CB-839 在 MDS 模型中的作用机制并研究临床前疗效；以及 (3) 测试 CB-839 组合的治疗效果；与5-氮杂胞苷在中危和高危MDS患者中进行I/II期临床试验，我们将具体确定该组合消除MDS干细胞的功效，并分析对其的影响。由于 DNA 的高甲基化是 MDS 的一个重要标志，因此两种低甲基化方法（通过不同的作用机制）的结合可能对 MDS 有效。这项工作将有助于更好地了解 MDS 的代谢途径。

项目成果

Amino acid metabolism in hematologic malignancies and the era of targeted therapy.

血液系统恶性肿瘤中的氨基酸代谢和靶向治疗时代。

• 发表时间: 2019
• 影响因子: 20.3
• 作者: Tabe, Yoko;Lorenzi, Philip L;Konopleva, Marina
• 通讯作者: Konopleva, Marina

Inhibition of FAO in AML co-cultured with BM adipocytes: mechanisms of survival and chemosensitization to cytarabine.

在与 BM 脂肪细胞共培养的 AML 中，FAO 的抑制作用：生存机制和对阿糖胞苷的化学敏化。

• 发表时间: 2018
• 影响因子: 4.6
• 作者: Tabe, Yoko;Saitoh, Kaori;Yang, Haeun;Sekihara, Kazumasa;Yamatani, Kotoko;Ruvolo, Vivian;Taka, Hikari;Kaga, Naoko;Kikkawa, Mika;Arai, Hajime;Miida, Takashi;Andreeff, Michael;Spagnuolo, Paul A;Konopleva, Marina
• 通讯作者: Konopleva, Marina

Novel Strategy for Untargeted Chiral Metabolomics using Liquid Chromatography-High Resolution Tandem Mass Spectrometry.

使用液相色谱-高分辨率串联质谱法进行非靶向手性代谢组学的新策略。

• DOI: 10.1021/acs.analchem.0c05325
• 发表时间: 2021-04-05
• 期刊: Analytical chemistry
• 影响因子: 7.4
• 作者: R. P;ey;ey;Meghan Collins;Xiyuan Lu;Shannon R. Sweeney;J. Chiou;A. Lodi;S. Tiziani
• 通讯作者: S. Tiziani

Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis in vitro.

异黄酮 ME-344 通过抑制 OXPHOS 和/或体外嘌呤生物合成来增强 Venetoclax 的抗 AML 活性。

• DOI: 10.1016/j.bcp.2023.115981
• 发表时间: 2023-12-09
• 期刊: Biochemical pharmacology
• 影响因子: 5.8
• 作者: K. Hurrish;Yongwei Su;Shraddha Patel;Cass;ra L. Ramage;ra;Jianlei Zhao;Brianna R. Temby;J. Carter;Holly Edwards;Steven A Buck;S;ra E. Wiley;ra;M. Hüttemann;Lisa Polin;Juiwanna Kushner;Sijana H Dzinic;Kathryn White;X. Bao;Jing Li;Jay Yang;Julie Boerner;Z. Hou;Gheath Al;S. Konoplev;Jonathan Busquets;S. Tiziani;L. Matherly;J. Taub;M. Konopleva;Y. Ge;Natalia Baran
• 通讯作者: Natalia Baran

Highly sensitive and selective determination of redox states of coenzymes Q9 and Q10 in mice tissues: Application of orbitrap mass spectrometry.

高灵敏度和选择性测定小鼠组织中辅酶 Q9 和 Q10 的氧化还原态：轨道阱质谱法的应用。

• DOI: 10.1016/j.aca.2018.01.066
• 发表时间: 2018-06-29
• 期刊: Analytica chimica acta
• 影响因子: 6.2
• 作者: Pandey R;Riley CL;Mills EM;Tiziani S
• 通讯作者: Tiziani S