Vismodegib as First-Line Treatment of Mutated Sonic Hedgehog Pathway in Adult Medulloblastoma
Waleed Kian, Laila C. Roisman, Iris M. Goldstein, Abed Abo-Quider, Benzion Samueli, Nadav Wallach, Farouq Alguayn, Walid Shalata, Dina Levitas, Olga Belochitski, Daniel Levin, Eyal Fenig, Konstantin Lavrenkov, Margarita Tokar, Nir Peled, Alexander Yakobson
Abstract
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.1,2 PTCH13 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.4-6 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% of MB cases. On the basis of gene expression profiling, four molecular subgroups of MB have been identified: WNT, SHH, group 3, and group 4.7 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%).8 Open in a separate window FIG 1. Graphic representation of sonic hedgehog (SHH) pathway. (1) HH ligand binding to PTCH1. (2) Binding of HH to PTCH1 releases SMO. (3) Showing the inhibition of SMO by vismodegib, which leads to inhibition of the whole pathway.