title: SDF-1 Blockade Enhances Anti-VEGF Therapy of Glioblastoma and Can Be Monitored by MRI.
abstract: Despite the approval of antiangiogenic therapy for glioblastoma multiforme (GBM) patients, survival benefits are still limited. One of the resistance mechanisms for antiangiogenic therapy is the induction of hypoxia and subsequent recruitment of macrophages by stromal-derived factor (SDF)-1α (CXCL-12). In this study, we tested whether olaptesed pegol (OLA-PEG, NOX-A12), a novel SDF-1α inhibitor, could reverse the recruitment of macrophages and potentiate the antitumor effect of anti-vascular endothelial growth factor (VEGF) therapy. We also tested whether magnetic resonance imaging (MRI) with ferumoxytol as a contrast agent could provide early information on macrophage blockade. Orthotopic human G12 glioblastomas in nude mice and rat C6 glioblastomas were employed as the animal models. These were treated with bevacizumab or B-20, both anti-VEGF antibodies. Rats were MR imaged with ferumoxytol for macrophage detection. Tumor hypoxia and SDF-1α expression were elevated by VEGF blockade. Adding OLA-PEG to bevacizumab or B-20 significantly prolonged the survival of rodents bearing intracranial GBM compared with anti-VEGF therapy alone. Intratumoral CD68+ tumor associated macrophages (TAMs) were increased by VEGF blockade, but the combination of OLA-PEG + VEGF blockade markedly lowered TAM levels compared with VEGF blockade alone. MRI with ferumoxytol as a contrast agent noninvasively demonstrated macrophage reduction in OLA-PEG + anti-VEGF-treated rats compared with VEGF blockade alone. In conclusion, inhibition of SDF-1 with OLA-PEG inhibited the recruitment of TAMs by VEGF blockage and potentiated its antitumor efficacy in GBM. Noninvasive MRI with ferumoxytol as a contrast agent provides early information on the effect of OLA-PEG in reducing TAMs.
authors.affiliation: Department of Radiation Oncology, Stanford University, A246, 1050A Arastradero Rd., Palo Alto, CA 94304-1334, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Deng
authors.affiliation: Department of Radiation Oncology, Stanford University, A246, 1050A Arastradero Rd., Palo Alto, CA 94304-1334, USA.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Stafford
authors.affiliation: Department of Radiation Oncology, Stanford University, A246, 1050A Arastradero Rd., Palo Alto, CA 94304-1334, USA.
authors.forename: Shie-Chau
authors.initials: SC
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Stanford University, A246, 1050A Arastradero Rd., Palo Alto, CA 94304-1334, USA.
authors.forename: Sophia B
authors.initials: SB
authors.lastname: Chernikova
authors.affiliation: Department of Neurology, Stanford University School of Medicine, 875 Blake Wilbur Dr., Stanford, CA 94305, USA.
authors.forename: Milton
authors.initials: M
authors.lastname: Merchant
authors.affiliation: Department of Neurology, Stanford University School of Medicine, 875 Blake Wilbur Dr., Stanford, CA 94305, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Recht
authors.affiliation: Department of Radiation Oncology, Stanford University, A246, 1050A Arastradero Rd., Palo Alto, CA 94304-1334, USA. Electronic address: mbrown@stanford.edu.
authors.forename: J
authors.initials: J
authors.lastname: Martin Brown
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D052157:Aptamers, Nucleotide / Q000494:pharmacology; D000068258:Bevacizumab / Q000494:pharmacology; D015415:Biomarkers; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging; D009389:Neovascularization, Pathologic; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D052157:Aptamers, Nucleotide; D015415:Biomarkers; D054377:Chemokine CXCL12; C587878:NOX-A12; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab