New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of Pediatric Medulloblastoma

SIMPLE SUMMARY: Medulloblastoma is the most common pediatric brain tumor, comprising one-third of all pediatric brain tumors, and originating in the posterior fossa of the brain. The disease is categorized into four subtypes: WNT, Sonic hedgehog (SHH), Group 3, and Group 4. Each subtype has unique pathogenesis, biomarkers, prognosis, response to therapy, and potential for further pharmacologic investigation. For example, it has recently been found that tumors in the SHH group arise due to aberrant persistence of defective cells of the embryonic germinal layer of the cerebellum. Herein, we review the recent critical advancements in understanding the four molecular subtypes that continue to shape our diagnostic, surgical, radiotherapeutic, and chemotherapeutic intervention and management to aid in treating pediatric medulloblastoma. We describe preclinical studies and clinical trials that aim to improve risk-stratification of disease, reduce therapy toxicity, and optimize the treatment of pediatric patients. ABSTRACT: Pediatric medulloblastoma (MB) is the most common pediatric brain tumor with varying prognoses depending on the distinct molecular subtype. The four consensus subgroups are WNT, Sonic hedgehog (SHH), Group 3, and Group 4, which underpin the current 2021 WHO classification of MB. While the field of knowledge for treating this disease has significantly advanced over the past decade, a deeper understanding is still required to improve the clinical outcomes for pediatric patients, who are often vulnerable in ways that adult patients are not. Here, we discuss how recent insights into the pathogenesis of pediatric medulloblastoma have directed current and future research. This review highlights new developments in understanding the four molecular subtypes’ pathophysiology, epigenetics, and therapeutic targeting. In addition, we provide a focused discussion of recent developments in imaging, and in the surgery, chemotherapy, and radiotherapy of pediatric medulloblastoma. The article includes a brief explanation of healthcare costs associated with medulloblastoma treatment.