title: Combined VEGF and CXCR4 antagonism targets the GBM stem cell population and synergistically improves survival in an intracranial mouse model of glioblastoma.
abstract: Glioblastoma recurrence involves the persistence of a subpopulation of cells with enhanced tumor-initiating capacity (TIC) that reside within the perivascular space, or niche (PVN). Anti-angiogenic therapies may prevent the formation of new PVN but have not prevented recurrence in clinical trials, suggesting they cannot abrogate TIC activity. We hypothesized that combining anti-angiogenic therapy with blockade of PVN function would have superior anti-tumor activity. We tested this hypothesis in an established intracranial xenograft model of GBM using a monoclonal antibody specific for murine and human VEGF (mcr84) and a Protein Epitope Mimetic (PEM) CXCR4 antagonist, POL5551. When doses of POL5551 were increased to overcome an mcr84-induced improvement in vascular barrier function, combinatorial therapy significantly inhibited intracranial tumor growth and improved survival. Anti-tumor activity was associated with significant changes in tumor cell proliferation and apoptosis, and a reduction in the numbers of perivascular cells expressing the TIC marker nestin. A direct effect on TICs was demonstrated for POL5551, but not mcr84, in three primary patient-derived GBM isolates. These findings indicate that targeting the structure and function of the PVN has superior anti-tumor effect and provide a strong rationale for clinical evaluation of POL5551 and Avastin in patients with GBM.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.
authors.forename: Amy
authors.initials: A
authors.lastname: Barone
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Sengupta
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Warrington
authors.affiliation: BRIGHT Institute , Washington University School of Medicine, St. Louis, MO. Molecular Imaging Center, Mallinckrodt Institute of Radiology , Washington University School of Medicine, St. Louis, MO.
authors.forename: Erin
authors.initials: E
authors.lastname: Smith
authors.affiliation: Center for Neuro-Oncology, Dana Farber/Brigham and Women's Cancer Center, Boston, MA. Division of Neuro-Oncology, Department of Neurology, Brigham and Women's Hospital, Boston, MA.
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX.
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
authors.affiliation: PolyPhor Ltd, Hegenheimermattweg 125 CH-4123 Allschwil, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Romagnoli
authors.affiliation: PolyPhor Ltd, Hegenheimermattweg 125 CH-4123 Allschwil, Switzerland.
authors.forename: Garry
authors.initials: G
authors.lastname: Douglas
authors.affiliation: PolyPhor Ltd, Hegenheimermattweg 125 CH-4123 Allschwil, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Chevalier
authors.affiliation: PolyPhor Ltd, Hegenheimermattweg 125 CH-4123 Allschwil, Switzerland.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Bauer
authors.affiliation: PolyPhor Ltd, Hegenheimermattweg 125 CH-4123 Allschwil, Switzerland.
authors.forename: Klaus
authors.initials: K
authors.lastname: Dembowsky
authors.affiliation: BRIGHT Institute , Washington University School of Medicine, St. Louis, MO. Molecular Imaging Center, Mallinckrodt Institute of Radiology , Washington University School of Medicine, St. Louis, MO. Department of Cell Biology and Physiology , Washington University School of Medicine, St. Louis, MO. Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: David
authors.initials: D
authors.lastname: Piwnica-Worms
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO. Department of Anatomy and Neurobiology , Washington University School of Medicine, St. Louis, MO.
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Rubin
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000008:administration & dosage / Q000494:pharmacology; D011897:Random Allocation; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; C527276:CXCR4 protein, human; C572528:POL5551; D011506:Proteins; D019718:Receptors, CXCR4; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A