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.