Novel Models of Group 4 Medulloblastoma for Accelerated Preclinical Discovery

Abstract Background Medulloblastoma (MB) is the most common malignant pediatric brain tumor. MB is subdivided into four main subgroups: SHH, WNT, Group 3 (G3-MB) and Group 4 (G4-MB). Despite advancements in treatment regimens, 30% of MB patients succumb to metastasis and treatment relapse. G4-MB represents a large subset of patients ranging from high risk to good prognosis. G4-MB tumor biology remains poorly understood and molecularly ambiguous. Pre-clinical development is obstructed by suboptimal existing models. here, we report the development of novel G4-MB models with the capacity for in vitro propagation and preclinical drug screening. Methods Two G4-MB tumor lines (MBT375 and MBT417) were derived from patient tumors and characterized by NanoString, RNA-seq and DNA methylation profiling. Subsequently, these models were serially engrafted in mice or cultured in vitro. G4-MB models were assessed for stem cell marker BMI1 expression levels and subsequent dose-response and synergy assays were performed in comparison to neural stem cells with BMI1 targeted drugs. G4-MB cells were transduced with firefly luciferase for optimized in vivo modelling. Results We present two novel G4-MB patient-derived orthotopic mouse models: MBT375 (subtype VIII) and MBT417 (subtype VI), with the capacity for short-term in vitro propagation, genetic manipulation, and improved tumorigenicity. Importantly, MBT375-engrafted mice reliably develop spinal metastatic disease. We demonstrate in vitro that repurposing G3-MB specific BMI1-targeted therapeutic strategies is a rational approach for the most common and often difficult-to-treat MB subtype. Conclusions We developed novel G4-MB models serving as in vitro discovery platforms to identify novel cancer-selective treatment modalities.