Abstract
Medulloblastoma is an embryonal tumor that shows a predilection for distant metastatic spread and leptomeningeal seeding. For most patients, optimal management of medulloblastoma includes maximum safe resection followed by adjuvant craniospinal irradiation (CSI) and chemotherapy. Although CSI is crucial in treating medulloblastoma, the realization that medulloblastoma is a heterogeneous disease comprising four distinct molecular subgroups (wingless [WNT], sonic hedgehog [SHH], Group 3 [G3], and Group 4 [G4]) with distinct clinical characteristics and prognoses has refocused efforts to better define the optimal role of CSI within and across disease subgroups. The ability to deliver clinically relevant CSI to preclinical models of medulloblastoma offers the potential to study radiation dose and volume effects on tumor control and toxicity in these subgroups and to identify subgroup-specific combination adjuvant therapies. Recent efforts have employed commercial image-guided small animal irradiation systems as well as custom approaches to deliver accurate and reproducible fractionated CSI in various preclinical models of medulloblastoma. Here, we provide an overview of the current clinical indications for, and technical aspects of, irradiation of pediatric medulloblastoma. We then review the current literature on preclinical modeling of and treatment interventions for medulloblastoma and conclude with a summary of challenges in the field of preclinical modeling of CSI for the treatment of leptomeningeal seeding tumors.
Highlights
Medulloblastoma is a posterior fossa embryonal tumor of neuroectodermal origin that is thought to arise from progenitor cells present during early brain development [1,2,3]
Efforts have been directed toward maintaining or improving overall survival rates while minimizing treatment-related toxicity. These efforts have primarily focused on modifications to radiation therapy (RT) approaches that can be broadly grouped as follows: investigations of the effects of adding concurrent and/or adjuvant chemotherapy regimens [9,10]; investigations of the effects of delaying or omitting RT for very young children [11,12,13,14]; investigations of the effects of reductions in the RT dose and field size [15,16]; and, over the past decade, the identification of distinct molecular subgroups of medulloblastoma with specific alterations that drive tumorigenesis, facilitating the identification of new therapeutic targets and enhanced risk stratification [17,18,19]
Several groups have developed murine models of medulloblastoma, primarily in an effort to create preclinical testing tools. These models range from genetically engineered murine models (GEMMs) to patient-derived orthotopic xenografts (PDOXs) [71]
Summary
Medulloblastoma is a posterior fossa embryonal tumor of neuroectodermal origin that is thought to arise from progenitor cells present during early brain development [1,2,3]. Advances in molecular pathology have revealed significant heterogeneity within this cerebellar tumor and have identified four distinct subgroups (wingless [WNT], sonic hedgehog [SHH], Group 3 [G3], and Group 4 [G4]). This has significant implications for future applications of surgery, chemotherapy, and radiation therapy (RT) [6]. The review concludes with a summary of outstanding questions in the field of preclinical modeling of RT for pediatric brain tumors and a consideration of future directions for treating leptomeningeal seeding tumors with these approaches
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