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

描述（由申请人提供）：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组成性激活是癌症（包括GBM）的一个标志。GBM显示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的转录因子。重要的是，STAT-3最近被证明是GBM攻击性的主要调节剂。Janus激酶1（JAK 1）和JAK 2是STAT-3激活的关键酪氨酸激酶，在GBM中也被不适当地激活。我们最近已经证明了JAK/STAT-3通路的内源性调节因子的异常表达。活化的STAT-3的蛋白抑制剂（PIAS 3），活化的STAT-3的负调节剂，在GBM中不存在或以非常低的水平表达，并且CK 2，一种对增强JAK 1、JAK 2和STAT-3活化重要的蛋白激酶，在GBM中过表达。本申请的前提是JAK/STAT-3信号传导轴在GBM背景下被不适当地激活，并且治疗干预将对GBM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期的影响。将检查胶质瘤组织中该途径的激活状态，并分析与PIAS 3和/或CK 2、肿瘤分级、GBM亚型（经典、间充质、前神经、神经）和患者总体生存期的相关性。目的2将阐明JAK/STAT-3通路在GBM中被激活的机制，并测试激活的JAK 1/JAK 2的有效抑制剂AZD 1480在胶质瘤异种移植物和胶质母细胞瘤干细胞（GBM-SC）中的影响。还将检查当PIAS 3或CK 2表达被调节时异种移植物和GBM-SC基因表达和/或行为如何受到影响的分析。目的3将阐明激活的JAK/STAT-3在体内胶质瘤发生中的作用，以及JAK 1/JAK 2抑制剂AZD 1480在恶性胶质瘤临床前模型中的疗效。将评价AZD 1480单独治疗和与替莫唑胺/放射联合治疗的人胶质瘤异种移植物的存活率、肿瘤生长率、侵袭和血管生成的变化。还将评价同基因GBM模型。所提出的研究是创新的和新颖的，因为它们是JAK 1、JAK 2、STAT-3、PIAS 3和CK 2之间的相互关系的第一次全面分析，以及它们的表达水平是否预测患者生存和/或作为GBM的预后因素。对GBM组织样品、TCGA和Oncomine数据、人胶质瘤异种移植物、GBM-SC、胶质瘤临床前模型和AZD 1480的使用的分析将为GBM患者中JAK/STAT-3信号传导轴的拟议治疗干预提供基础。

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.