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, Joshua B. Rubin

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)9811-9822
Number of pages12
JournalOncotarget
Volume5
Issue number20
StatePublished - 2014

Fingerprint

Glioblastoma
Vascular Endothelial Growth Factor A
Stem Cells
Survival
Population
Neoplasms
Recurrence
Nestin
Neoplastic Stem Cells
Heterografts
Blood Vessels
Epitopes
Therapeutics
Monoclonal Antibodies
Cell Proliferation
Clinical Trials
Apoptosis
POL5551
Growth
Proteins

Keywords

  • CXCR4
  • Glioblastoma
  • Perivascular
  • Stem cells
  • VEGF

ASJC Scopus subject areas

  • Oncology

Cite this

Combined VEGF and CXCR4 antagonism targets the GBM stem cell population and synergistically improves survival in an intracranial mouse model of glioblastoma. / Barone, Amy; Sengupta, Rajarshi; Warrington, Nicole M.; Smith, Erin; Wen, Patrick Y.; Brekken, Rolf A.; Romagnoli, Barbara; Douglas, Garry; Chevalier, Eric; Bauer, Michael P.; Dembowsky, Klaus; Piwnica-Worms, David; Rubin, Joshua B.

In: Oncotarget, Vol. 5, No. 20, 2014, p. 9811-9822.

Research output: Contribution to journalArticle

Barone, A, Sengupta, R, Warrington, NM, Smith, E, Wen, PY, Brekken, RA, Romagnoli, B, Douglas, G, Chevalier, E, Bauer, MP, Dembowsky, K, Piwnica-Worms, D & Rubin, JB 2014, 'Combined VEGF and CXCR4 antagonism targets the GBM stem cell population and synergistically improves survival in an intracranial mouse model of glioblastoma', Oncotarget, vol. 5, no. 20, pp. 9811-9822.
Barone, Amy ; Sengupta, Rajarshi ; Warrington, Nicole M. ; Smith, Erin ; Wen, Patrick Y. ; Brekken, Rolf A. ; Romagnoli, Barbara ; Douglas, Garry ; Chevalier, Eric ; Bauer, Michael P. ; Dembowsky, Klaus ; Piwnica-Worms, David ; Rubin, Joshua B. / Combined VEGF and CXCR4 antagonism targets the GBM stem cell population and synergistically improves survival in an intracranial mouse model of glioblastoma. In: Oncotarget. 2014 ; Vol. 5, No. 20. pp. 9811-9822.
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