The hedgehog (Hh) signaling pathway is activated in many types of cancer and therefore presents an attractive target for new anticancer agents. Here we show that mebendazole (MBZ), a benzamidazole with a long history of safe use against nematode infestations and hydatid disease, potently inhibited Hh signaling and slowed the growth of Hh-driven human medulloblastoma cells at clinically attainable concentrations. As an antiparasitic, MBZ avidly binds nematode tubulin and causes inhibition of intestinal microtubule synthesis. In human cells, MBZ suppressed the formation of the primary cilium, a microtubule-based organelle that functions as a signaling hub for Hh pathway activation. The inhibition of Hh signaling by MBZ was unaffected by mutants in the gene that encodes the Hh pathway signaling protein SMO, which are selectively propagated in cell clones that survive treatment with the Hh inhibitor vismodegib. Combination of vismodegib and MBZ resulted in additive Hh signaling inhibition. Because MBZ can be safely administered to adults and children at high doses over extended time periods, we propose that MBZ could be rapidly repurposed and clinically tested as a prospective therapeutic agent for many tumors that are dependent on Hh signaling.

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<p>Supplementary Figure 1: (A) Survival of mice with DAOY-derived orthotopic tumors at 25 mg/kg MBZ (n=4) or mock-treated (n=3). One mouse from the mock treatment group did not develop symptoms of a growing brain tumor, and was euthanized after surviving for more than six months. This mouse was not found to have a brain tumor, and was therefore omitted from this analysis. (B) RNA was harvested from untreated and treated tumors and assessed by qRT-PCR for expression of GLI1, PTCH1, and PTCH2.</p>

<p>Supplementary Figure 1: (A) Survival of mice with DAOY-derived orthotopic tumors at 25 mg/kg MBZ (n=4) or mock-treated (n=3). One mouse from the mock treatment group did not develop symptoms of a growing brain tumor, and was euthanized after surviving for more than six months. This mouse was not found to have a brain tumor, and was therefore omitted from this analysis. (B) RNA was harvested from untreated and treated tumors and assessed by qRT-PCR for expression of GLI1, PTCH1, and PTCH2.</p>