Casein Kinase 1 alpha Agonists as Novel Medulloblastoma Inhibitors

Medulloblastoma is the most common childhood brain cancer, forty percent of which is caused by activated Hedgehog (HH) or WNT signaling pathways.  These two signaling pathways are also two of the most common pathways activated in cancer, providing the driving force for the growth and maintenance of cancer stem cells -- the cells proposed to be resistant to chemotherapy and radiotherapy that ultimately leads to cancer relapse.  Thus the targeted attenuation of these signaling pathways could tremendously improve the outcome of such therapy. We have identified pyrvinium, a FDA approved pinworm drug, as a small-molecule inhibitor of both HH and WNT signaling through activation of a common cellular target. We will demonstrate that this shared signaling component, is a novel therapeutic target in medulloblastoma. We will also test the possibility of repurposing pyrvinium (and structural analogs) to inhibit HH-driven medulloblastoma in mouse models. The outcome of this proposal has significant potential to provide therapeutics for medulloblastoma as well as other cancers, and the prior FDA approval of pyrvinium for an alternate indication presents a rapid way forward for its path to the clinic.