Molecular Targeted Therapies: Time for a Paradigm Shift in Medulloblastoma Treatment?

Abstract

Medulloblastoma is a rare malignancy of the posterior cranial fossa. Although until now considered a single disease, according to the current WHO classification, it is a heterogeneous tumor that comprises multiple molecularly defined subgroups, with distinct gene expression profiles, pathogenetic driver alterations, clinical behaviors and age at onset. Adult medulloblastoma, in particular, is considered a rarer “orphan” entity in neuro-oncology practice because while treatments have progressively evolved for the pediatric population, no practice-changing prospective, randomized clinical trials have been performed in adults. In this scenario, the toughest challenge is to transfer the advances in cancer genomics into new molecularly targeted therapeutics, to improve the prognosis of this neoplasm and the treatment-related toxicities. Herein, we focus on the recent advances in targeted therapy of medulloblastoma based on the new and deeper knowledge of disease biology.

Adult Medulloblastoma: Updates on Current Management and Future Perspectives

“…Vismodegib and sonidegib, two highly selective SHH inhibitors targeting the SMO receptor, have demonstrated a favorable toxicity profile and an encouraging efficacy in preclinical and clinical trials of patients affected by MB with activation of the SHH pathway [ 28 , 29 , 30 , 31 , 32 , 33 , 126 , 127 , 128 , 129 ].…”

Metabolic determinants of stemness in medulloblastoma

“…Targeted therapies for WNT and SHH MB entail inhibiting the major pathways implicated in their tumourigenesis[ 62 ]. As an example, the use of Smo inhibitors in the SHH MB group has been linked to tumour suppression in mouse models, and tumour regression in MB patients[ 62 , 63 ]. On the other hand, research on WNT MBs has focused on nuclear β-catenin inhibitors, leading to reduced cell migration and invasion[ 63 , 64 ].…”

“…In Groups 3 and 4 there are no major advances in targeted therapy as they have a low somatic mutation rate[ 61 , 63 ]. Group 3 MB is characterised by MYC oncogene amplification, so some epigenetic MYC inhibitors, such as histone deacetylases (HDACs) and bromodomain inhibitors, have been tested[ 65 , 66 ].…”