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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（由申请人提供）：多形性胶质母细胞瘤（GBM）是一种侵袭性CNS恶性肿瘤，很少可治愈。弥漫性脑侵袭是这种癌症的一个标志。在分子水平上，表皮生长因子受体（EGFR）在决定许多GBM的生理学方面起着核心作用。EGFR基因扩增在GBM中是常见的，并且经常伴有外显子2-7的框内缺失，这产生受体的截短的组成型活性形式（EGFRvIII）。由于EGFR和EGFRvIII对GBM细胞生理学的深远影响，EGFR选择性酪氨酸激酶抑制剂（TKI）和其他EGFR靶向治疗药物已被用于治疗这些肿瘤。疗效已得到证实;然而，GBM通常无法控制。我们已经鉴定了尿激酶型纤溶酶原激活物受体（uPAR）作为细胞信号传导受体，当EGFR信号传导被中和或当GBM细胞用EGFR靶向治疗剂处理时，其可以被激活以支持GBM细胞生长和存活。uPAR细胞信号系统的激活可增加GBM细胞的迁移和侵袭。在表达EGFRvIII的GBM细胞中，涉及EGFRvIII和uPAR的串扰途径可能是激活促有丝分裂转录因子STAT 5 B并实现高度侵袭性表型所必需的。当EGFR在不存在EGFRvIII的情况下扩增时，也可能发生类似的串扰途径。该研究项目的目标是表征uPAR作为与GBM细胞中的EGFR协同作用的受体以及作为可能允许GBM在用EGFR靶向治疗剂治疗的患者中脱离控制的受体的作用。了解uPAR在GBM细胞中的机制将有助于合理设计uPAR靶向治疗药物，这些药物可单独使用或与EGFR靶向药物联合用于GBM患者。在目标1中，我们将研究多个模型系统，包括作为异种移植物繁殖的人GBM，以测试以下假设：uPAR信号传导的激活构成GBM细胞逃避EGFR靶向治疗控制的重要途径。在目标2中，我们将在GBM细胞中在分子水平上表征uPAR-EGFR串扰，并测试用于中和这种串扰的候选治疗方法。在目标3中，我们测试是否无意中激活了在用EGFR靶向治疗剂处理的GBM细胞中，uPA-uPAR系统诱导有利于细胞迁移和侵袭的表型变化。在目的4中，我们探讨uPAR和EGFR在原发性和复发性人GBM的手术标本中的关系。我们还将应用量子点免疫荧光显微镜在单细胞水平上探测人类GBM标本中uPAR信号的证据。虽然这个项目有一个基本的科学基础，我们的目标是高度翻译。最终，我们的目标是完成必要的临床前研究，以证明靶向uPAR用于GBM的治疗开发。