Genetic modification of neurons to express bevacizumab for local anti-angiogenesis treatment of glioblastoma

M. J. Hicks, K. Funato, L. Wang, E. Aronowitz, J. P. Dyke, D. J. Ballon, D. F. Havlicek, E. Z. Frenk, B. P. De, M. J. Chiuchiolo, D. Sondhi, N. R. Hackett, S. M. Kaminsky, V. Tabar, Ronald Crystal

Research output: Contribution to journalArticle

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Abstract

The median survival of glioblastoma multiforme (GBM) is approximately 1 year. Following surgical removal, systemic therapies are limited by the blood-brain barrier. To circumvent this, we developed a method to modify neurons with the genetic sequence for therapeutic monoclonal antibodies using adeno-associated virus (AAV) gene transfer vectors, directing persistent, local expression in the tumor milieu. The human U87MG GBM cell line or patient-derived early passage GBM cells were administered to the striatum of NOD/SCID immunodeficient mice. AAVrh.10BevMab, an AAVrh.10-based vector coding for bevacizumab (Avastin), an anti-human vascular endothelial growth factor (VEGF) monoclonal antibody, was delivered to the area of the GBM xenograft. Localized expression of bevacizumab was demonstrated by quantitative PCR, ELISA and western blotting. Immunohistochemistry showed that bevacizumab was expressed in neurons. Concurrent administration of AAVrh.10BevMab with the U87MG tumor reduced tumor blood vessel density and tumor volume, and increased survival. Administration of AAVrh.10BevMab 1 week after U87MG xenograft reduced growth and increased survival. Studies with patient-derived early passage GBM primary cells showed a reduction in primary tumor burden with an increased survival. These data support the strategy of AAV-mediated central nervous system gene therapy to treat GBM, overcoming the blood-brain barrier through local, persistent delivery of an anti-angiogenesis monoclonal antibody.

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalCancer Gene Therapy
Volume22
Issue number1
DOIs
Publication statusPublished - 28 Jan 2015
Externally publishedYes

Fingerprint

Glioblastoma
Neurons
Dependovirus
Survival
Monoclonal Antibodies
Tumor Burden
Blood-Brain Barrier
Heterografts
Therapeutics
Vascular Tissue Neoplasms
SCID Mice
Genetic Therapy
Bevacizumab
Neoplasms
Central Nervous System
Western Blotting
Enzyme-Linked Immunosorbent Assay
Immunohistochemistry
Cell Line
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

Cite this

Genetic modification of neurons to express bevacizumab for local anti-angiogenesis treatment of glioblastoma. / Hicks, M. J.; Funato, K.; Wang, L.; Aronowitz, E.; Dyke, J. P.; Ballon, D. J.; Havlicek, D. F.; Frenk, E. Z.; De, B. P.; Chiuchiolo, M. J.; Sondhi, D.; Hackett, N. R.; Kaminsky, S. M.; Tabar, V.; Crystal, Ronald.

In: Cancer Gene Therapy, Vol. 22, No. 1, 28.01.2015, p. 1-8.

Research output: Contribution to journalArticle

Hicks, MJ, Funato, K, Wang, L, Aronowitz, E, Dyke, JP, Ballon, DJ, Havlicek, DF, Frenk, EZ, De, BP, Chiuchiolo, MJ, Sondhi, D, Hackett, NR, Kaminsky, SM, Tabar, V & Crystal, R 2015, 'Genetic modification of neurons to express bevacizumab for local anti-angiogenesis treatment of glioblastoma', Cancer Gene Therapy, vol. 22, no. 1, pp. 1-8. https://doi.org/10.1038/cgt.2014.58
Hicks, M. J. ; Funato, K. ; Wang, L. ; Aronowitz, E. ; Dyke, J. P. ; Ballon, D. J. ; Havlicek, D. F. ; Frenk, E. Z. ; De, B. P. ; Chiuchiolo, M. J. ; Sondhi, D. ; Hackett, N. R. ; Kaminsky, S. M. ; Tabar, V. ; Crystal, Ronald. / Genetic modification of neurons to express bevacizumab for local anti-angiogenesis treatment of glioblastoma. In: Cancer Gene Therapy. 2015 ; Vol. 22, No. 1. pp. 1-8.
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