ET-51 * COMBINED THERAPY WITH A NOVEL CXCR4 ANTAGONIST AND AN ANTI-VEGF ANTIBODY IMPAIRS THE GROWTH OF GLIOMAS

BACKGROUND: Expression of chemokine receptor CXCR4 and its ligand stromal cell-derived factor-1α (SDF-1α) is enhanced in glioblastoma, including at invasive edges, and associated with proliferation, invasion and angiogenesis (Zagzag, 2008; Ehtesham, 2013; Gagliardi, 2014). Using Protein Epitope Mimetics technology (Robinson, 2008), Polyphor Ltd. has developed selective, highly potent CXCR4 antagonists (De Marco, 2006), e.g., POL5551 (Ki: 0.5 nM). To address the problem of resistance to antiangiogenic therapy, we sought to determine whether POL5551 could inhibit the growth and/or invasion of gliomas in vivo. METHODS: Female adult C57BL/6 mice were implanted orthotopically with 1 x 105 CT-2A or GL261 glioma cells. On day 14, mice were randomized into 4 groups: 1) control, 2) POL5551 (5 mg/kg s.c.) twice daily, 3) anti-murine VEGF monoclonal antibody B20-4.1.1 (Genentech Inc.) (5 mg/kg i.p.) twice weekly (Bagri, 2010) and 4) combined POL5551 and B20-4.1.1. On day 28, brain tissues were processed, sections analyzed for tumor volume and invasion (HE 45.8 nM) than in brain adjacent to tumor (45 ± 4.8; 23.7) or normal brain (21 ± 1.5; 11.1) and sufficient to account for its biological effects. CONCLUSIONS: Although combined therapy did not reduce significantly glioma invasion, it did impair the growth of CT-2A and GL261 gliomas by 69.8% and 59.9%, respectively. Our results suggest the potential utility of POL5551 as adjunct therapy for glioblastoma.