Novel CXCR4 Therapeutics to Block Bevacizumab-Induced Glioma Dissemination.

阻断贝伐珠单抗诱导的神经胶质瘤传播的新型 CXCR4 疗法。

基本信息

批准号：
8249597
负责人：
DAVID ZAGZAG
金额：
$ 25.35万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8249597
关键词：
Adult Angiogenesis Inhibitors Animal Model Antibodies Avastin Behavior Biodistribution Biological Blood Brain Brain Neoplasms Brain Part CXCR4 Receptors Cells Cerebral hemisphere Clinic Clinical Treatment Clinical Trials Data Development Diffuse Disease Distant Drug Delivery Systems Edema Employee Strikes Environment FDA approved G-Protein-Coupled Receptors Glioblastoma Glioma Grant Growth Harvest Human Hypoxia Infiltration Invaded Malignant - descriptor Mediating Medical center Modality Modeling Molecular Mus Neoplasms New York Outcome Patients Pattern Play Progression-Free Survivals Property Quality of life Recurrence Relapse Research Role Schedule Stromal Cell-Derived Factor 1 Testing Therapeutic Translations Transmembrane Domain Treatment Failure Tumor Cell Invasion Universities Up-Regulation base bevacizumab cancer therapy chemokine receptor follow-up glioma cell line improved in vivo inhibitor/antagonist insight neoplastic cell neovasculature novel novel therapeutics outcome forecast pre-clinical receptor research study small molecule steroid dependence subcutaneous tumor

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is the most common and malignant primary intracranial human neoplasm. Anti-(R) angiogenic therapy with bevacizumab (Avastin) has become standard therapy in recurrent high-grade gliomas in adults. Patients at New York University Langone Medical Center and elsewhere continue to receive bevacizumab because of (i) marked improvement in quality of life, (ii) although transient, a demonstrable increase in progression-free survival and overall survival compared to historical controls, and (iii) relief from steroid dependence due to diminished tumor edema (Narayana, 2009). We and others have observed that the pattern of relapse in bevacizumab-treated GBM patients is often characterized by local, as well as distant infiltration of the brain by the tumor. We have conducted a proof-of-concept experiment with mouse bevacizumab (anti-VEGF antibody B20-4.1.1 from Genentech) to determine whether bevacizumab induces invasive growth of GL261 glioma cells in the brain of mice. GL261 gliomas treated with mouse bevacizumab showed increased infiltration of the brain highly similar to that observed in human patients receiving the humanized bevacizumab antibody. The chemokine receptor CXCR4 plays a critical role in glioma invasion. We intend to use two experimental in vivo murine glioma models (GL261 and CT-2A) to screen novel and extremely potent CXCR4 inhibitors (POL5551 and POL6326) developed by Polyphor Ltd. for their efficacy in blocking bevacizumab-induced glioma dissemination. CXCR4 antagonists are being used increasingly in the clinic for cancer therapy (Wong, 2008) and could potentially control the invasive behavior of CXCR4- positive glioma cells, prolonging bevacizumab's efficacy and improving the prognosis of glioma patients. PUBLIC HEALTH RELEVANCE: (R) Anti-angiogenic therapy with bevacizumab (Avastin) has become standard therapy in recurrent high-grade gliomas in adults. We will use novel and potent CXCR4 antagonists POL5551 and POL6326 to block bevacizumab-induced glioma dissemination.

描述（由申请人提供）：胶质母细胞瘤（GBM）是最常见和恶性的原发性颅内人类肿瘤。使用贝伐单抗（Avastin）进行抗（R）血管生成治疗已成为成人复发性高级别神经胶质瘤的标准治疗。纽约大学朗格尼医学中心和其他地方的患者继续接受贝伐珠单抗治疗，因为（i）生活质量显着改善，（ii）与历史对照相比，尽管短暂，但无进展生存期和总生存期明显增加，以及（ iii) 由于肿瘤水肿减轻而缓解类固醇依赖性（Narayana，2009）。我们和其他人观察到，接受贝伐珠单抗治疗的 GBM 患者的复发模式通常以肿瘤对大脑的局部和远处浸润为特征。我们用小鼠贝伐单抗（Genentech 的抗 VEGF 抗体 B20-4.1.1）进行了概念验证实验，以确定贝伐单抗是否会诱导小鼠大脑中 GL261 神经胶质瘤细胞的侵袭性生长。用小鼠贝伐单抗治疗的 GL261 神经胶质瘤显示出大脑浸润增加，与接受人源化贝伐单抗抗体的人类患者中观察到的情况高度相似。趋化因子受体CXCR4在神经胶质瘤侵袭中发挥着关键作用。我们打算使用两种实验性体内小鼠神经胶质瘤模型（GL261 和 CT-2A）来筛选 Polyphor Ltd. 开发的新型且极其有效的 CXCR4 抑制剂（POL5551 和 POL6326），以了解其在阻止贝伐珠单抗诱导的神经胶质瘤传播方面的功效。 CXCR4拮抗剂在临床上越来越多地用于癌症治疗（Wong，2008），并且有可能控制CXCR4阳性神经胶质瘤细胞的侵袭行为，延长贝伐珠单抗的疗效并改善神经胶质瘤患者的预后。公共卫生相关性：(R) 贝伐单抗（阿瓦斯丁）抗血管生成治疗已成为成人复发性高级别神经胶质瘤的标准治疗。我们将使用新型有效的 CXCR4 拮抗剂 POL5551 和 POL6326 来阻止贝伐珠单抗诱导的神经胶质瘤扩散。