Bevacizumab suppresses neuroblastoma progression in the setting of minimal disease

Surgery. 2008 Aug;144(2):269-75. doi: 10.1016/j.surg.2008.04.009.

Abstract

Background: We hypothesized that vascular endothelial growth factor (VEGF) contributes to autocrine stimulation of neuroblastoma and that inhibition of its signaling pathway contributes to the anticancer activity of bevacizumab, an anti-VEGF monoclonal antibody.

Methods: For in vitro studies, 2 neuroblastoma cell lines, CHLA-255 and NB1691, were treated with VEGF+/-bevacizumab. For in vivo studies, disseminated neuroblastoma was established by intravenous administration of luciferase-expressing tumor cells in SCID mice prior to bevacizumab treatment.

Results: Exogenous VEGF increased cell counts after 48 h (NB1691: 58,878 +/- 8279 vs 137,500 +/- 13,108 cells, P < .001; CHLA: 1.56 x 10(6) +/- 866 vs 1.81 x 10(6) +/- 2550 cells, P <.001); the addition of bevacizumab abrogated this stimulation. In vivo, mice with disseminated disease treated twice weekly with intraperitoneal bevacizumab had a decreased tumor burden at day 14 and prolonged survival (NB1691: 50 +/- 2 vs 43 +/- 2 days, P < .001; CHLA: 53 +/- 3 vs 42 +/- 1 days, P = .006). Interestingly, VEGF and basic fibroblast growth factor expression was increased in treated NB1691 tumors, which likely occurred in response to VEGF signaling inhibition.

Conclusion: Our results suggest that VEGF has a role in neuroblastoma autocrine signaling. Maintenance therapy with bevacizumab may be useful for disease suppression after maximal cytoreductive therapy; however, upregulation of proangiogenic factors may provide resistance to this approach, which suggests that maximal antitumor efficacy may require combination therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Autocrine Communication
  • Bevacizumab
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Disease Progression
  • Fibroblast Growth Factor 2 / metabolism
  • Humans
  • Mice
  • Mice, SCID
  • Neuroblastoma / drug therapy
  • Neuroblastoma / pathology*
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Signal Transduction
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A / immunology
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor A / pharmacology

Substances

  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Vascular Endothelial Growth Factor A
  • Fibroblast Growth Factor 2
  • Bevacizumab
  • Receptors, Vascular Endothelial Growth Factor