Repurposing mebendazole for the treatment of medulloblastoma.

T he current treatment for medulloblastoma—resection, radiation, and chemotherapy—negatively affects neurocognitive development and fails to ensure survival beyond 10 years for about 40% of children. Among the 4 molecular subtypes of this disease, the group 3 subtype has an especially poor prognosis. Recently, Bai and colleagues demonstrated compelling preclinical evidence for using the microtubule inhibitory drug mebendazole (MBZ) to treat several molecular subtypes of medulloblastoma, including group 3. As a long-standing antihelminthic drug, MBZ has the advantage of a low-toxicity profile in children compared with other microtubule inhibitors such as vincristine and paclitaxel. As a lipophilic agent with a low molecular weight, MBZ has the additional advantage of blood-brain barrier permeability. Previous studies suggest that MBZ acts as an inhibitor of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2), the primary receptor mediating the effects of VEGF. This study reveals the antiangiogenic effect of MBZ in medulloblastoma preclinical mouse models and its encouraging impact on overall survival. The authors used 3 orthotopic models of medulloblastoma: a genetic model of the sonic hedgehog (SHH) molecular subtype consisting of allografts from spontaneous medulloblastomas in patched (PTCH)1/2, p532/2 mice; a model of therapy-resistant SHH consisting of allografts from tumors resistant to the hedgehog pathway inhibitor vismodegib; and a xenograft model with human group 3 medulloblastoma cells, D425 MB, implanted into the cerebellum. Implanted cells were transduced with firefly luciferase–expressing lentivirus for in vivo bioluminescent imaging. Mice in the treatment group received daily oral gavage of MBZ (50 mg/ kg) starting 5 days after tumor cell implantation. Tumor vasculature in brain tissue from treated animals was compared with that of phosphate-buffered saline–treated control animals by immunostaining for the endothelial marker CD31. The impact of MBZ on the kinase activity of VEGFR2 was assessed by Western blots for VEGFR2 autophosphorylation after VEGF stimulation of human umbilical vein endothelial cells and by a cell-free kinase assay.