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

Amy Barone, Rajarshi Sengupta, Nicole M. Warrington, Erin Smith, Patrick Y. Wen, Rolf A. Brekken, Barbara Romagnoli, Garry Douglas, Eric Chevalier, Michael P. Bauer, Klaus Dembowsky, David Piwnica-Worms and Joshua B. Rubin _

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

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Abstract

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.


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