Bevacizumab suppresses neuroblastoma progression in the setting of minimal disease.

Abstract

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. 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. 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. 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.