Vismodegib as First-Line Treatment of Mutated Sonic Hedgehog Pathway in Adult Medulloblastoma.

Medulloblastoma (MB) is an aggressive, primitive neuroectodermal tumor mainly affecting pediatric patients and with frequent involvement of the posterior fossa and extraneural metastasis. MB has a low incidence in adults (, 1% of adult brain tumors) and treatment protocols for adult patients have been adapted from pediatric oncology. PTCH1 tumor suppressor gene functions as an inhibitor of smoothened (SMO) and downstream sonic hedgehog (SHH) signaling. SHH ligand connects to the receptor on PTCH1, which results in SMO suppression (Fig 1). PTCH1 germline inactivating mutations are associated with Gorlin syndrome, which is associated with a high incidence of basal cell carcinoma (BCC) and predisposition to MB. This association is strengthened because somatic mutations that inactivate PTCH1 are frequently found in the sporadic forms of these types of cancers. Genomic analyses of MB have identified PTCH1 a mutation incidence of 3%-7% ofMB cases. On the basis of gene expression profiling, four molecular subgroups of MB have been identified: WNT, SHH, group 3, and group 4. The prognosis for patients within the SHH subgroup MB differs greatly upon TP53 mutation status, wherein patients with wild-type TP53 have a significantly better 5-year overall survival rate (76%) compared with those with TP53 mutation (41%).