Abstract
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 10
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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 (H&E), vascular density (CD105) and apoptosis (caspase 3), and results compared (ANOVA). RESULTS: In CT-2A glioma-bearing mice, combined therapy significantly reduced tumor volume (17.3 ± 2.4 mm
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, mean ± S.E.M.) compared with controls (57.2 ± 6.4, p < 0.01) and POL5551 (55.8 ± 11.2, p < 0.01), but not B20-4.1.1 (31.9 ± 8.7). The depth of tumor invasion was reduced by 47.5% (p < 0.07) with POL5551, but by only 10.3% with B20-4.1.1, and 24.4% with combined therapy. Comparable, but not statistically significant, results were obtained with GL261 gliomas. The concentration of POL5551 was higher in glioma tissues (87 ± 25.4 ng/g; 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.