Bevacizumab suppresses neuroblastoma progression in the setting of minimal disease.

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.