Novel CXCR4 Therapeutics to Block Bevacizumab-Induced Glioma Dissemination.

描述(申请人提供)：胶质母细胞瘤(GBM)是最常见和最恶性的原发于颅内的肿瘤。贝伐单抗(阿瓦斯丁)的抗(R)血管生成疗法已经成为成人复发性高级别胶质瘤的标准疗法。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单抗治疗，因为(I)生活质量显著改善，(Ii)尽管是暂时的，但与历史对照相比，无进展存活率和总存活率明显增加，以及(Iii)由于肿瘤水肿减轻而减轻了对类固醇的依赖(Narayana，2009)。我们和其他人已经观察到，贝伐单抗治疗的GBM患者的复发模式通常以肿瘤对大脑的局部和远处侵袭为特征。我们用小鼠贝伐单抗(Genentech公司的抗血管内皮生长因子抗体B20-4.1.1)进行了概念验证实验，以确定贝伐单抗是否能诱导小鼠脑内GL261胶质瘤细胞的侵袭性生长。用小鼠贝伐单抗治疗的GL261胶质瘤显示出与接受人源化贝伐单抗治疗的人类患者非常相似的脑组织浸润性增加。趋化因子受体CXCR4在脑胶质瘤侵袭中发挥重要作用。我们打算使用两个实验性的体内小鼠胶质瘤模型(GL261和CT-2A)来筛选Polyphor Ltd.开发的新型和极其有效的CXCR4抑制剂(POL5551和POL6326)，以研究它们阻止贝伐单抗诱导的胶质瘤转移的有效性。CXCR4拮抗剂正越来越多地用于临床癌症治疗(Wong，2008)，并有可能控制CXCR4阳性胶质瘤细胞的侵袭行为，延长贝伐单抗的疗效并改善胶质瘤患者的预后。

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.