The Neurodevelopmental and Molecular Landscape of Medulloblastoma Subgroups: Current Targets and the Potential for Combined Therapies

Abstract

Medulloblastoma is the most common malignant pediatric brain tumor and is associated with significant morbidity and mortality in the pediatric population. Despite the use of multiple therapeutic approaches consisting of surgical resection, craniospinal irradiation, and multiagent chemotherapy, the prognosis of many patients with medulloblastoma remains dismal. Additionally, the high doses of radiation and the chemotherapeutic agents used are associated with significant short- and long-term complications and adverse effects, most notably neurocognitive delay. Hence, there is an urgent need for the development and clinical integration of targeted treatment regimens with greater efficacy and superior safety profiles. Since the adoption of the molecular-based classification of medulloblastoma into wingless (WNT) activated, sonic hedgehog (SHH) activated, group 3, and group 4, research efforts have been directed towards unraveling the genetic, epigenetic, transcriptomic, and proteomic profiles of each subtype. This review aims to delineate the progress that has been made in characterizing the neurodevelopmental and molecular features of each medulloblastoma subtype. It further delves into the implications that these characteristics have on the development of subgroup-specific targeted therapeutic agents. Furthermore, it highlights potential future avenues for combining multiple agents or strategies in order to obtain augmented effects and evade the development of treatment resistance in tumors.

Overcoming Treatment Resistance in Medulloblastoma: Underlying Mechanisms and Potential Strategies

“…Just like the other groups, Group 4 is also categorized into different subgroups with distinct genetic hallmarks. Herein, the subgroups 4α, 4β, and 4γ are characterized by MYCN amplification, SCNAIP duplication, and CDK6 amplification, respectively [ 27 ]. They all carry similar prognoses, with a 5-year survival rate of around 70–80% [ 18 ].…”

“…In this context, Ramaswamy et al confirmed that the molecular subtype of medulloblastoma at recurrence is consistent with that of the original tumor [ 83 ]. This might be related to the fact that different molecular subtypes have different neurodevelopmental origins [ 27 ]. However, despite this lack of subtype switching, the recurrent tumors display significant divergence from the distribution of cellular states and genetic footprint of the primary tumor [ 82 ].…”

“…Clinical trials targeting inhibition of downstream targets like GLI in SMO-mutated resistant medulloblastoma via Silmitasertib, a potent and selective casein kinase 2 inhibitor (NCT03904862) and Samotolisib, a PI3K inhibitor (NCT03213678 and NCT03155620), have shown promising results (Figure 4). Finally, the direct inhibition of GLI through the use of GLI antagonist 61 (GANT61) or arsenic trioxide (ATO) has shown great promise against therapy-resistant medulloblastoma [27]. Additionally, targeting the epigenetic regulator of GLI expression can also be utilized through the inhibition of BRD4 using JQ1 and CK2 using silmitasertib.…”