Oncotarget

Research Papers:

Combined VEGF and CXCR4 antagonism targets the GBM stem cell population and synergistically improves survival in an intracranial mouse model of glioblastoma

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Oncotarget. 2014; 5:9811-9822. https://doi.org/10.18632/oncotarget.2443

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Amy Barone1,*, Rajarshi Sengupta1,*, Nicole M. Warrington1, Erin Smith2,3, Patrick Y. Wen4,5, Rolf A. Brekken6, Barbara Romagnoli7, Garry Douglas7, Eric Chevalier7, Michael P. Bauer7, Klaus Dembowsky7, David Piwnica-Worms2,3,8,9 and Joshua B. Rubin1,10

1 Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO

2 BRIGHT Institute , Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO

3 Molecular Imaging Center, Mallinckrodt Institute of Radiology , Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO

4 Center for Neuro-Oncology, Dana Farber/Brigham and Women’s Cancer Center, Brookline Ave, Boston, MA

5 Division of Neuro-Oncology, Department of Neurology, Brigham and Women’s Hospital, Brookline Ave, Boston, MA

6 Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Harry Hines Blvd. Dallas, TX

7 PolyPhor Ltd, Hegenheimermattweg 125 CH-4123 Allschwil, Switzerland

8 Department of Cell Biology & Physiology , Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO

9 Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Holcombe Dr., Houston, TX

10 Department of Anatomy and Neurobiology , Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO

* These authors contributed equally to this work

Correspondence:

Joshua B. Rubin, email:

Keywords: CXCR4, VEGF, perivascular, glioblastoma, stem cells

Received: August 22, 2014 Accepted: September 08, 2014 Published: September 09, 2014

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.