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

Simple Summary Medulloblastoma is the most common malignant brain tumor in the pediatric population. Despite the utilization of aggressive treatment modalities, including surgery, chemotherapy, and radiation therapy, patients with medulloblastoma still have a poor prognosis. Moreover, these modalities are associated with dramatic life-long complications. Hence, this calls for the development of novel therapeutic agents that can more effectively and safely target this tumor and improve the survival and quality of life for patients. The molecular-based classification of medulloblastoma into WNT activated, SHH activated, group 3, and group 4 opened the door for research endeavors that aim to study the specific cellular, molecular, and neurodevelopmental characteristics of each subtype. This review aims to summarize the literature on the different profiles of these subtypes, elaborate on the pharmacologic therapies that have been investigated to target each, and suggest potential combination therapies that can offer superior outcomes. 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.