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

// Amy Barone 1,* , Rajarshi Sengupta 1,* , Nicole M. Warrington 1 , Erin Smith 2,3 , Patrick Y. Wen 4,5 , Rolf A. Brekken 6 , Barbara Romagnoli 7 , Garry Douglas 7 , Eric Chevalier 7 , Michael P. Bauer 7 , Klaus Dembowsky 7 , David Piwnica-Worms 2,3,8,9 and Joshua B. Rubin 1,10 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.