A Novel Cxcr4 Antagonist Interferes With Antivascular Endothelial Growth Factor Therapy-Induced Glioma Dissemination

Background: Resistance to antiangiogenic therapy (AT) in patients with glioblastoma (GBM) treated with bevacizumab (BEV) is characterized by local recurrence and distant dissemination of gliomas associated with remodeling of tumor vessels and pronounced hypoxia known to promote glioma cell invasion. Expression of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor-1α (SDF-1α) is enhanced in invading tumor cells (CXCR4) and neurons and blood vessels (SDF-1α) in GBM and associated with tumor hypoxia, proliferation, invasion and angiogenesis. Using Protein Epitope Mimetics (PEM) technology (Robinson JA et al., 2008), Polyphor Ltd. has developed selective, highly potent CXCR4 antagonists (De Marco SJ et al., 2006) (U.S. Patent no. 8,716,242), such as POL5551. To address the problem of resistance to AT, we sought to determine whether combined therapy (CTx) with POL5551 and the murine equivalent of BEV (antibody B20-4.1.1) could inhibit the invasion and associated pathologic characteristics of gliomas in vivo. Methods: Adult C57BL/6 mice implanted orthotopically with syngeneic CT-2A or GL261 glioma cells were randomized on day 14 into 4 groups: 1) control, 2) POL5551 (5 mg/kg s.c.), 3) anti-murine vascular endothelial growth factor (VEGF) monoclonal antibody B20-4.1.1 (5 mg/kg i.p.; Genentech Inc.) (Bagri A et al., 2010) and 4) combined POL5551 and B20-4.1.1 (CTx). On day 28, brain tissues were processed, sections analyzed for tumor volume and invasiveness (Sottoriva A et al., 2010) (HE May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A20.