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：
9023503
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 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9023503
关键词：
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 Gefitinib Gene Amplification Genomic Instability Glioblastoma Goals Grant Growth Health Human Immunofluorescence Microscopy Integrins Laboratories Ligand Binding Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Membrane Proteins 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 Cell 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 Therapeutic 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 neoplastic cell outcome forecast preclinical study promoter protein function receptor targeted treatment 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）：多形胶质母细胞瘤（GBM）是一种侵略性的中枢神经系统恶性肿瘤，很少可以治愈。弥漫性大脑侵袭是这种癌症的标志。在分子水平上，EGF受体（EGFR）在确定许多GBM的生理学方面起着核心作用。 EGFR基因扩增在GBM中很常见，并且经常伴随着2-7外显子的框架缺失，该删除产生了受体（EGFRVIII）的截断且组成型活性形式。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靶向疗法已被用来治疗这些肿瘤。已经证明了功效；但是，GBM通常从控制中逃脱。我们已经确定了尿激酶型纤溶酶原激活剂受体（UPAR）为一种细胞信号受体，当EGFR信号传导中和时，可能会激活以支持GBM细胞生长和存活，或用EGFR靶向靶向治疗剂处理GBM细胞时。 UPAR细胞信号系统的激活可能会增加GBM细胞迁移和侵袭。在表达EGFRVIII的GBM细胞中，涉及EGFRVIII和UPAR的串扰途径对于激活有丝分裂转录因子，STAT5B并实现了高度攻击性的表型可能至关重要。当在没有EGFRVIII的情况下扩增EGFR时，也可能会发生类似的串扰途径。该研究项目的目的是表征UPAR作为与EGFR在GBM细胞中协同作用的受体的作用，以及可能允许GBMS在接受EGFR靶向疗法治疗的患者中逃脱控制的受体。了解GBM细胞中的UPAR机制将促进可以独立使用或与GBM患者结合使用EGFR靶向药物的UPAR靶向治疗的合理设计。在AIM 1中，我们将研究多个模型系统，包括传播为异种移植物的人类GBM，以检验以下假设：UPAR信号传导的激活构成了GBM细胞通过EGFR-Target-Targeting Therapeutics从控制中逃脱的重要途径。在AIM 2中，我们将表征UPAR-EGFR串扰，在GBM细胞中的分子水平上以及测试候选治疗方法中和以中和该串扰。在AIM 3中，我们测试是否无意激活用EGFR靶向疗法处理的GBM细胞中的UPA-UPAR系统诱导了有利于细胞迁移和侵袭的表型变化。在AIM 4中，我们探讨了UPAR和EGFR在原发性和经常性人类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探测单细胞水平的人类GBM标本中UPAR信号传导的证据。尽管该项目具有基础科学基础，但我们的目标是高度转化的。最终，我们的目标是完成临床前研究，以证明将UPAR靶向GBM的治疗性开发是合理的。