Targeting the JAK/STAT-3 Pathway Signaling Axis in Glioma

靶向胶质瘤中的 JAK/STAT-3 通路信号轴

• 批准号: 8434816
• 负责人: Etty N Benveniste
• 金额: $ 28.57万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434816
• 关键词: Affect; Apoptotic; Behavior; Biochemical; Biological Assay; Biological Process; Cell Proliferation; Clinical; Clinical Trials; Foundations; Gene Expression; Genetic; Glioblastoma; Glioma; Gliomagenesis; Growth; Human; Immunoblotting; Immunocompetent; In Situ; Injection of therapeutic agent; Interleukin-6; JAK2 gene; Janus kinase 1; Lead; Ligation; Maintenance; Malignant Glioma; Malignant Neoplasms; Mesenchymal; Modeling; Molecular Profiling; Neuraxis; Normal Cell; Nude Mice; Pathway interactions; Patients; Phenotype; Pre-Clinical Model; Principal Investigator; Prognostic Factor; Protein Kinase; Protein Tyrosine Kinase; Protein-Serine-Threonine Kinases; Proteins; Radiation; Radiation Tolerance; Reporting; Role; Signal Pathway; Signal Transduction; Stat3 protein; Stem cells; Survival Analysis; Survival Rate; Techniques; Testing; The Cancer Genome Atlas; Therapeutic Intervention; Time; Tissue Sample; Tissues; Tyrosine Phosphorylation; Xenograft procedure; angiogenesis; cytokine; human PIAS3 protein; human data; in vivo; inhibitor/antagonist; innovation; interest; new therapeutic target; novel; programs; protein expression; protein inhibitors of activated STAT; relating to nervous system; response; temozolomide; transcription factor; tumor; tumor growth; upstream kinase

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is a malignancy of the central nervous system that is nearly universally fatal. Constitutive activation of tyrosine phosphorylation signaling pathways is one hallmark of cancers, including GBMs. GBMs show elevated levels and persistent activation of Signal Transducer and Activator of Transcription-3 (STAT-3), a transcription factor that drives expression of genes that regulate anti-apoptotic responses, angiogenesis, cell proliferation and signal transduction. Importantly, STAT-3 was recently shown to be a master regulator of GBM aggressiveness. Janus Kinase 1 (JAK1) and JAK2, tyrosine kinases critical for STAT-3 activation, are also inappropriately activated in GBMs. We have recently demonstrated aberrant expression of endogenous regulators of the JAK/STAT-3 pathway. Protein Inhibitor of Activated STAT-3 (PIAS3), a negative regulator of activated STAT-3, is absent or expressed at very low levels in GBMs, and CK2, a protein kinase important for potentiating JAK1, JAK2 and STAT-3 activation, is over-expressed in GBMs. The premise of this application is that the JAK/STAT-3 signaling axis is inappropriately activated in the context of GBMs, and that therapeutic intervention will be of clinical benefit to patients with GBMs. Aim 1 will characterize the JAK/STAT-3 Molecular Profiles in Primary GBM Tumors and Impact on Patient Survival. The activational status of this pathway in glioma tissues will be examined, and associations with PIAS3 and/or CK2, with tumor grade, GBM subtypes (classical, mesenchymal, proneural, neural), and overall patient survival analyzed. Aim 2 will elucidate the Mechanism(s) by Which the JAK/STAT-3 Pathway is activated in GBMs, and test the influence of AZD1480, a potent inhibitor of activated JAK1/JAK2, in glioma xenografts and glioblastoma stem cells (GBM-SC). Analysis of how xenograft and GBM-SC gene expression and/or behavior is affected when PIAS3 or CK2 expression is modulated will also be examined. Aim 3 will elucidate the Role of Activated JAK/STAT-3 on Gliomagenesis in Vivo, and the Efficacy of the JAK1/JAK2 Inhibitor AZD1480 in preclinical models of malignant gliomas. Changes in survival rates, tumor growth rates, invasion and angiogenesis for human glioma xenografts treated with AZD1480 alone and in conjunction with temozolomide/radiation will be evaluated. Syngeneic GBM models will also be evaluated. The proposed studies are innovative and novel because they are the first comprehensive analysis of the inter- relationships between JAK1, JAK2, STAT-3, PIAS3 and CK2, and whether their expression levels predict patient survival and/or serve as prognostic factors for GBMs. This analysis of GBM tissue samples, TCGA and Oncomine data, human glioma xenografts, GBM-SC, pre-clinical models of glioma and use of AZD1480 will provide the foundation for proposed therapeutic intervention of the JAK/STAT-3 signaling axis in patients with GBMs.

描述（由申请人提供）：胶质母细胞瘤（GBM）是几乎普遍致命的中枢神经系统的恶性肿瘤。酪氨酸磷酸化信号通路的组成型激活是包括GBM在内的癌症的一个标志。 GBM显示出升高的水平和持续激活的信号透射剂和转录3（Stat-3）激活因子，这是一种转录因子，该转录因子驱动调节抗凋亡反应，血管生成，细胞增殖和信号转导的基因表达。重要的是，STAT-3最近被证明是GBM侵略性的主要监管者。 Janus激酶1（JAK1）和JAK2，对于Stat-3激活至关重要的酪氨酸激酶，在GBMS中也不当激活。我们最近证明了JAK/Stat-3途径的内源性调节剂的异常表达。活化stat-3（PIAS3）的蛋白抑制剂是活化Stat-3的负调节剂，在GBMS中不存在或表达非常低的水平，而CK2（一种对增强JAK1，JAK1和Stat-3激活的蛋白激酶的蛋白激酶，GBMS都过度表达了。该应用的前提是，在GBMS的背景下，JAK/Stat-3信号轴不适当地激活，并且治疗干预对GBMS患者具有临床益处。 AIM 1将表征原发性GBM肿瘤中JAK/STAT-3分子特征，并影响患者生存。将检查该途径在神经胶质瘤组织中的活化状态，并与PIAS3和/或CK2与肿瘤等级，GBM亚型（经典，间充质，胸膜，神经，神经）和整体患者生存分析。 AIM 2将阐明在GBM中激活JAK/Stat-3途径的机制，并测试AZD1480的影响，AZD1480是激活JAK1/JAK2的有效抑制剂，在神经胶质瘤异种移植物和胶质母细胞瘤干细胞中的影响。当调制PIAS3或CK2表达时，对异种移植和GBM-SC基因表达和/或行为的影响分析也将被检查。 AIM 3将阐明活化的JAK/Stat-3在体内神经胶质作用方面的作用，以及JAK1/JAK2抑制剂AZD1480在恶性神经胶质瘤的临床前模型中的功效。单独使用AZD1480治疗的人神经胶质瘤异种移植物的生存率，肿瘤生长率，侵袭和血管生成的变化将评估，并与替莫唑胺/辐射结合使用。合成GBM模型也将进行评估。拟议的研究具有创新性和新颖性，因为它们是对JAK1，JAK2，STAT-3，PIAS3和CK2之间相互关系的首次综合分析，以及它们的表达水平是否可以预测患者的生存和/或作为GBM的预后因素。 GBM组织样品，TCGA和吞噬数据，人神经胶质瘤异种移植物，GBM-SC，神经胶质瘤前临床模型以及AZD1480的使用将为GBMS患者的JAK/Stat-3信号轴的拟议治疗干预奠定基础。