Bioinformatics analysis followed by studies in patient-derived xenograft (PDX) models were used to identify and validate CDK 4/6 inhibition as an effective therapeutic strategy for medulloblastoma, particularly group 3-amplified tumors that have the worst clinical prognosis. A protein interaction network derived from a mutagenesis model of medulloblastoma was used to identify potential novel therapeutic targets. The top hit from this analysis was validated using PDX models of medulloblastoma implanted subcutaneously in the flank and orthotopically in the cerebellum of mice. Informatics analysis identified the CDK4/6/CYCLIN D/RB pathway as a novel "druggable" pathway for multiple subgroups of medulloblastoma. Palbociclib, a highly specific inhibitor of CDK4/6, was found to inhibit RB phosphorylation and cause G arrest in PDX models of medulloblastoma. The drug caused rapid regression of Sonic hedgehog (SHH) and -amplified group 3 medulloblastoma subcutaneous tumors and provided a highly significant survival advantage to mice bearing-amplified intracranial tumors. Inhibition of CDK4/6 is potentially a highly effective strategy for the treatment of SHH and -amplified group 3 medulloblastoma..

The highly conserved Elongator complex is a translational regulator that plays a critical role in neurodevelopment, neurological diseases, and brain tumors. Numerous clinically relevant variants have been reported in the catalytic Elp123 subcomplex, while no missense mutations in the accessory subcomplex Elp456 have been described. Here, we identify ELP4 and ELP6 variants in patients with developmental delay, epilepsy, intellectual disability, and motor dysfunction. We determine the structures of human and murine Elp456 subcomplexes and locate the mutated residues. We show that patient-derived mutations in Elp456 affect the tRNA modification activity of Elongator in vitro as well as in human and murine cells. Modeling the pathogenic variants in mice recapitulates the clinical features of the patients and reveals neuropathology that differs from the one caused by previously characterized Elp123 mutations. Our study demonstrates a direct correlation between Elp4 and Elp6 mutations, reduced Elongator activity, and neurological defects. Foremost, our data indicate previously unrecognized differences of the Elp123 and Elp456 subcomplexes for individual tRNA species, in different cell types and in different key steps during the neurodevelopment of higher organisms.

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Background Novel targeted therapies for children diagnosed with medulloblastoma (MB), the most common malignant pediatric brain tumor, are urgently required. A major hurdle in the development of effective therapies is the impaired delivery of systemic therapies to tumor cells due to a specialized endothelial blood-brain barrier (BBB). Accordingly, the integrity of the BBB is an essential consideration in any preclinical model used for assessing novel therapeutics. This study sought to assess the functional integrity of the BBB in several preclinical mouse models of MB. Methods Dynamic contrast enhancement (DCE) magnetic resonance imaging (MRI) was used to evaluate blood-brain tumour-barrier (BBTB) permeability in a murine genetically engineered mouse model (GEMM) of SHH MB, patient-derived orthotopic xenograft (PDOX) models of MB (SHH and Gp3) and orthotopic transplantation of GEMM tumor cells, enabling a comparison of the direct effects of transplantation on the integrity of the BBTB. Immunofluorescence analysis was performed to compare the structural and sub-cellular features of tumor-associated vasculature in all models. Results Contrast enhancement was observed in all transplantation models of MB. No contrast enhancement was observed in the GEMM despite significant tumor burden. Cellular analysis of BBTB integrity revealed aberrancies in all transplantation models, correlating to the varying levels of BBTB permeability observed by MRI in these models. Conclusions These results highlight functional differences in the integrity of the BBTB and tumor vessel phenotype between commonly utilised preclinical models of MB, with important implications for the preclinical evaluation of novel therapeutic agents for MB.