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Targeting the Urokinase Receptor in Glioblastoma Multiforme

靶向多形性胶质母细胞瘤中的尿激酶受体

基本信息

批准号：
9215655
负责人：
STEVEN L. GONIAS
金额：
$ 32.16万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9215655
关键词：
Alpha Cell Applications Grants Basic Science Binding Sites Biological Models Brain Cell Line Cell Survival Cell physiology Cells Chemotherapy-Oncologic Procedure Critiques Diffuse Disease remission Doxycycline Drug Targeting EGF gene Epidermal Growth Factor Receptor Erlotinib Event Excision Exons Exposure to FPR2 gene Failure Financial compensation Foundations GPI Membrane Anchors Gefitinib Gene Amplification Genomic Instability Glioblastoma Goals Grant Growth Human Immunofluorescence Microscopy Integrins Laboratories Ligand Binding Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Molecular Multiprotein Complexes Mus Mutation Neuraxis Operative Surgical Procedures PTEN gene Pathway interactions Patients Pharmaceutical Preparations Phenotype Phosphorylation Physiology Play Population Publishing Quantum Dots Receptor Gene Receptor Protein-Tyrosine Kinases Receptor Signaling Recurrence Regulation Research Project Grants Resistance Role STAT5B gene Signal Pathway Signal Transduction Specimen Study models Suggestion System Technology Testing Time Tumor Suppressor Proteins Tyrosine Kinase Inhibitor Urokinase Plasminogen Activator Receptor Work Xenograft procedure cancer cell cell growth cell motility design drinking water drug development effective therapy epidermal growth factor receptor VIII extracellular gene product in vivo kinase inhibitor neoplastic cell new therapeutic target outcome forecast preclinical study promoter protein function public health relevance receptor targeted treatment therapeutic candidate therapeutic development transcription factor tumor tumor growth tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is an aggressive CNS malignancy, which is rarely curable. Diffuse brain invasion is a hallmark of this cancer. At the molecular level, the EGF receptor (EGFR) plays a central role in determining the physiology of many GBMs. EGFR gene amplification is common in GBM and frequently accompanied by an in-frame deletion of exons 2-7, which yields a truncated and constitutively active form of the receptor (EGFRvIII). Because of the profound effects of the EGFR and EGFRvIII on GBM cell physiology, EGFR-selective tyrosine kinase inhibitors (TKIs) and other EGFR-targeting therapeutics have been used to treat these tumors. Efficacy has been demonstrated; however, GBMs typically escape from control. We have identified the urokinase-type plasminogen activator receptor (uPAR) as a cell-signaling receptor that may become activated to support GBM cell growth and survival when EGFR signaling is neutralized or when GBM cells are treated with EGFR-targeting therapeutics. Activation of the uPAR cell-signaling system may increase GBM cell migration and invasion. In GBM cells, in which EGFRvIII is expressed, crosstalk pathways involving EGFRvIII and uPAR may be essential to activate the mitogenic transcription factor, STAT5B, and actualize a highly aggressive phenotype. Similar crosstalk pathways also may occur when the EGFR is amplified in the absence of EGFRvIII. The goal of this research project is to characterize the role of uPAR as a receptor that synergizes with the EGFR in GBM cells and as a receptor that may allow GBMs to escape from control in patients that are treated with EGFR-targeting therapeutics. Understanding uPAR mechanisms in GBM cells will facilitate rational design of uPAR-targeting therapeutics that could be used independently or in combination with EGFR-targeting drugs in patients with GBM. In Aim 1, we will study multiple model systems, including human GBMs that are propagated as xenografts, to test the hypothesis that activation of uPAR signaling constitutes an important pathway by which GBM cells escape from control by EGFR-targeting therapeutics. In Aim 2, we will characterize uPAR-EGFR crosstalk, at the molecular level in GBM cells, and test candidate therapeutic approaches for neutralizing this crosstalk. In Aim 3, we test whether inadvertent activation of the uPA-uPAR system, in GBM cells treated with EGFR-targeting therapeutics, induces phenotypic changes favoring cell migration and invasion. In Aim 4, we explore the relationship between uPAR and the EGFR in surgical specimens of primary and recurrent human GBMs. We also will apply quantum dot immunofluorescence microscopy to probe for evidence of uPAR signaling in human GBM specimens, at the single-cell level. Although this project has a basic science foundation, our objectives are highly translational. Ultimately, our goal is to complete the pre-clinical studies necessary to justify targeting uPAR for therapeutics development in GBM.

描述（申请人提供）：多形性胶质母细胞瘤（GBM）是一种侵袭性中枢神经系统恶性肿瘤，很难治愈。弥漫性脑浸润是这种癌症的特征。在分子水平上，EGF受体（EGFR）在决定许多GBMs的生理过程中起着核心作用。EGFR基因扩增在GBM中很常见，并且经常伴随着框架内外显子2-7的缺失，从而产生截断和构成活性形式的受体（EGFRvIII）。由于EGFR和EGFRvIII对GBM细胞生理的深刻影响，EGFR选择性酪氨酸激酶抑制剂（TKIs）和其他EGFR靶向疗法已被用于治疗这些肿瘤。疗效已得到证实；然而，GBMs通常会失控。我们已经确定尿激酶型纤溶酶原激活剂受体（uPAR）是一种细胞信号受体，当EGFR信号被中和或当GBM细胞接受EGFR靶向治疗时，uPAR可能被激活以支持GBM细胞的生长和存活。uPAR细胞信号系统的激活可能会增加GBM细胞的迁移和侵袭。在EGFRvIII表达的GBM细胞中，涉及EGFRvIII和uPAR的串扰通路可能是激活有丝分裂转录因子STAT5B和实现高度侵袭性表型所必需的。当EGFR在缺乏EGFRvIII的情况下被放大时，类似的串扰通路也可能发生。本研究项目的目标是描述uPAR作为一种与GBM细胞中的EGFR协同作用的受体的作用，以及作为一种可能使GBM在接受EGFR靶向治疗的患者中失控的受体。了解uPAR在GBM细胞中的作用机制将有助于合理设计uPAR靶向治疗药物，这些药物可以单独使用，也可以与egfr靶向药物联合用于GBM患者。在Aim 1中，我们将研究多种模型系统，包括作为异种移植物繁殖的人类GBM，以验证uPAR信号的激活是GBM细胞逃避egfr靶向治疗控制的重要途径的假设。在Aim 2中，我们将在GBM细胞的分子水平上表征uPAR-EGFR串扰，并测试候选治疗方法来中和这种串扰。在Aim 3中，我们测试无意中激活的