Targeting the Sonic Hedgehog Pathway in Brain Cancers: Advances, Limitations, and Future Directions

Aberrant signaling of the sonic hedgehog (SHH) pathway can result in increased cellular proliferation and cancer. SHH subgroup medulloblastomas (MBs) comprise about a third of the molecular types of this malignant brain tumor, and unfortunately drug resistance limits the efficacy of vismodegib and sonidegib, the only FDA-approved therapies directly targeting the SHH pathway. Emerging literature also suggests important roles of SHH signaling in meningiomas and in glioblastoma multiforme (GBM), the latter being an extremely aggressive tumor and the most common primary brain tumor in adults. This chapter illustrates the roles of the SHH pathway in the pathogenesis of MB, GBM, and meningiomas. In addition, we will cover the existing challenges with current drug therapies and detail recent findings in the regulation of the SHH pathway, findings which advance the discovery of novel drug therapies.