A novel therapeutic combination for neuroblastoma

Abstract

BACKGROUND: High-risk cases of neuroblastoma have poor survival rates, and novel therapies are needed. Vandetanib (ZD6474, Zactima) is an inhibitor of the vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection (RET) tyrosine kinases, which have each been implicated in neuroblastoma pathogenesis. The authors hypothesized that vandetanib combined with 13-cis-retinoic acid (CRA), a differentiating agent used in most current neuroblastoma treatment regimens, would be effective against neuroblastoma tumor models. METHODS: The authors evaluated the effects of vandetanib with and without CRA on RET phosphorylation and on the proliferation and survival of human neuroblastoma cell lines in vitro. Using a subcutaneous mouse xenograft model of human neuroblastoma, they analyzed tumors treated with CRA, vandetanib, and the combination of vandetanib plus CRA for growth, gross and histologic appearance, vascularity, and apoptosis. RESULTS: Vandetanib treatment inhibited RET phosphorylation and resulted in induction of apoptosis in the majority of neuroblastoma cell lines in vitro, whereas CRA treatment induced morphologic differentiation and cell-cycle arrest. Treatment with vandetanib plus CRA resulted in more significant reduction in neuroblastoma cell viability than either alone. In a mouse xenograft model, the combination of vandetanib with CRA demonstrated significantly more growth inhibition than either alone, via both reduction in tumor vascularity and induction of apoptosis. CONCLUSIONS: Vandetanib induces neuroblastoma tumor cell death in vitro and reduces tumor growth and vascularity in vivo. The combination of vandetanib with CRA was more effective in reducing tumor growth than either treatment alone. The antitumor effects of vandetanib plus CRA suggest a novel combination for use in neuroblastoma patients.

Quantitative Phosphoproteomic Analysis Identifies Activation of the RET and IGF-1R/IR Signaling Pathways in Neuroblastoma

“…Vandetanib acts by inhibiting several tyrosine kinases including Ret, VEGFR2, EGFR, BRK, TIE2, and members of the EPH receptor kinase and Src kinase families [76,77]. Treatment of NB10 cells with Vandetanib resulted in a decrease in cell viability at doses of 1 to 10μM (Figure 6A), in keeping with prior reports [78,79]. Treatment of additional NB cell lines with Vandetanib demonstrated a similar effect, with the most potent growth inhibitory effect noted in NB7 cells (Figure 6B).…”

The combination of the novel glycolysis inhibitor 3-BrOP and rapamycin is effective against neuroblastoma

“…Six to eight week-old NOD/SCID/IL2R-gamma mice (stock # 005557, Jackson laboratories, Bar Harbor, ME) were inoculated subcutaneously into the right flank with 10 7 SK-N-SH neuroblastoma tumor cells as previously described [45]. Once tumors were palpable (~300 mm 3 ), mice were randomly assigned to treatment with 20 mg/kg of 3-BrOP or with vehicle, once daily by tail vein injection.…”

New aspects of neuroblastoma treatment: ASPHO 2011 symposium review

“…Studies have demonstrated that RET is required for retinoic acid-induced neuroblastoma differentiation [66], and that RET inhibition is effective in neuroblastoma preclinical models [67]. Other recent studies have identified the polo-like kinase 1 (PLK1) as a potential target for neuroblastoma therapy, based on screens of a library of kinase inhibitors in neuroblastoma preclinical models [68], while a screening study using an siRNA library identified the checkpoint kinase 1 (CHK1) as a potential target [69].…”