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)是一种几乎普遍致命的中枢神经系统恶性肿瘤。酪氨酸磷酸化信号通路的结构性激活是包括GBMS在内的癌症的一个特征。基底膜表现出信号转导和转录激活因子-3(STAT-3)的水平升高和持续激活，STAT-3是一种转录因子，驱动调控抗凋亡反应、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侵袭性的主要调节因子。Janus Kinase 1(JAK1)和JAK2，这两个对STAT-3激活至关重要的酪氨酸激酶，在GBM中也被不适当地激活。我们最近发现JAK/STAT-3通路的内源性调节因子表达异常。激活的STAT-3的负调节因子--激活的STAT-3的蛋白抑制因子(PIAS3)在基底膜中缺失或低水平表达，而在基底膜中高表达的CK2是一种重要的增强JAK1、JAK2和STAT-3激活的蛋白激酶。这一应用的前提是JAK/STAT-3信号轴在GBMS的背景下被不适当地激活，并且治疗干预将对GBMS患者的临床有益。目的1研究JAK/STAT-3在原发基底膜肿瘤中的表达及其对患者生存的影响。我们将检测该通路在胶质瘤组织中的激活状态，并分析PIAS3和/或CK2与肿瘤分级、GBM亚型(经典、间充质、神经、神经)和总体患者生存的关系。目的2阐明JAK/STAT-3通路在胶质母细胞瘤中被激活的机制(S)，并检测激活的JAK1/JAK2的有效抑制剂AZD1480对胶质瘤移植瘤和胶质母细胞瘤干细胞的影响。当PIAS3或CK2表达被调控时，异种移植和GBM-SC基因的表达和/或行为如何受到影响的分析也将被检验。目的3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在恶性胶质瘤临床前模型中的疗效。将评估单独使用AZD1480以及与替莫唑胺/放射联合治疗的人胶质瘤移植瘤的存活率、肿瘤生长率、侵袭性和血管生成的变化。同基因的GBM模型也将得到评估。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可以预测患者的生存和/或作为GBM的预后因素。这种对GBM组织样本、TCGA和Oncomine数据、人胶质瘤异种移植、GBM-SC、胶质瘤临床前模型和AZD1480的使用的分析，将为拟议的对GBMS患者JAK/STAT-3信号轴的治疗干预提供基础。 公共卫生相关性：JAK/STAT-3通路是引起人们对GBM感兴趣的一个至关重要的信号通路，我们假设JAK是GBM的新治疗靶点。我们将首次测试有效的JAK1/JAK2抑制剂AZD1480：通过抑制上游激酶JAK1和JAK2，AZD1480治疗将导致抑制STAT-3的激活、基因表达以及促进和维持胶质瘤形成的生物学功能。总的来说，这项提案的结果将为在GBM患者的临床试验中使用JAK/STAT-3抑制剂提供令人信服的理由。