Targeting Canonical and Noncanonical Hedgehog Signaling Pathways in Cancer
Larsen, Andrew R
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The hedgehog (Hh) signaling pathway is activated in many types of cancer and therefore presents an attractive target for new anticancer agents. In the studies described here I demonstrate how mebendazole (MBZ), a benzimidazole 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 FDA approved Hh inhibitor 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, I propose that MBZ could be rapidly repurposed and clinically tested as a prospective therapeutic agent for the many tumors that are dependent on Hh signaling. One important genetic regulator of Hedgehog signaling is the tumor suppressor PTCH1. In addition to my studies of the canonical Hedgehog pathway and its inhibition by MBZ, I have also investigated a non-canonical pathway mediated by a novel PTCH1 homolog recently identified in our lab. I present evidence that this new gene, PTCH53, functions both in the canonical Hedgehog pathway and in a noncanonical Hh pathway that links p53 with innate immunity.