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: 8237478
• 负责人: Etty N Benveniste
• 金额: $ 30.4万
• 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/8237478
• 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. PUBLIC HEALTH RELEVANCE: One critically important signaling pathway gaining interest in the context of GBMs is the JAK/STAT-3 pathway, and we hypothesize that JAKs are novel therapeutic targets in GBMs. We will test for the first time the potent JAK1/JAK2 inhibitor AZD1480: by inhibiting the upstream kinases JAK1 and JAK2, AZD1480 treatment will lead to inhibition of STAT-3 activation, gene expression, and the biological functions that promote and sustain gliomagenesis. Collectively, the results from this proposal will provide a compelling rationale for the use of JAK/STAT-3 inhibitors in clinical trials for patients with GBMs.

描述（申请人提供）：胶质母细胞瘤（GBM）是一种中枢神经系统恶性肿瘤，几乎是普遍致命的。酪氨酸磷酸化信号通路的组成性激活是癌症的一个标志，包括GBMs。GBMs显示信号换能器和转录激活因子-3 （STAT-3）水平升高和持续激活，STAT-3是一种转录因子，可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侵袭性的主要调节剂。Janus Kinase 1 （JAK1）和JAK2是STAT-3激活的关键酪氨酸激酶，在GBMs中也被不适当激活。我们最近证实了JAK/STAT-3通路内源性调控因子的异常表达。活化STAT-3蛋白抑制剂（PIAS3）是活化STAT-3的负调节因子，在GBMs中缺失或表达水平极低，而CK2是一种增强JAK1、JAK2和STAT-3活化的重要蛋白激酶，在GBMs中过度表达。该应用的前提是JAK/STAT-3信号轴在GBMs中被不适当激活，并且治疗干预将对GBMs患者具有临床益处。目的1将描述原发性GBM肿瘤中JAK/STAT-3分子谱及其对患者生存的影响。该通路在胶质瘤组织中的激活状态将被检测，并与PIAS3和/或CK2、肿瘤分级、GBM亚型（经典、间充质、前神经、神经）和患者总体生存率的关系进行分析。目的2将阐明JAK/STAT-3通路在GBMs中被激活的机制，并测试AZD1480（一种激活JAK1/JAK2的有效抑制剂）对胶质瘤异种移植物和胶质母细胞瘤干细胞（GBM-SC）的影响。当PIAS3或CK2表达被调节时，异种移植物和GBM-SC基因表达和/或行为是如何受到影响的分析也将被检查。目的3将阐明激活的JAK/STAT-3在体内胶质瘤形成中的作用，以及JAK1/JAK2抑制剂AZD1480在临床前恶性胶质瘤模型中的疗效。将评估AZD1480单独治疗和替莫唑胺/放疗联合治疗的人类胶质瘤异种移植物的存活率、肿瘤生长速率、侵袭和血管生成的变化。还将对同系GBM模型进行评价。这些研究具有创新性和新颖性，因为它们首次全面分析了JAK1、JAK2、STAT-3、PIAS3和CK2之间的相互关系，以及它们的表达水平是否能预测患者的生存和/或作为GBMs的预后因素。对GBM组织样本、TCGA和Oncomine数据、人类胶质瘤异种移植物、GBM- sc、胶质瘤临床前模型和AZD1480的分析将为GBM患者JAK/STAT-3信号轴的治疗干预提供基础。