Medulloblastoma is a malignant pediatric brain cancer that arises from developing cerebellum. Our preliminary data show that medulloblastoma cell survival critically depends on persistent activity of neurodevelopmental pathways that favor proliferation and block differentiation. Small molecule inhibition of the sonic hedgehog or notch pathway kill medulloblastoma cells more effectively than standard chemotherapy agents. Our broad hypothesis is that both hedgehog and notch signaling are necessary for medulloblastoma, but neither is sufficient. Our long term goal is develop and utilize genetically precise mouse models of medulloblastoma to provide insight into disease pathogenesis and understand which molecular pathways are appropriate for therapeutic targeting. We have developed the ND2:SmoA1 mouse model that faithfully recapitulates human medulloblastoma with a 48% tumor incidence and a mean age of diagnosis of 25.7 weeks. In this model, Nmyc and notch signaling are increased in cerebellar tumors but not in non-neoplastic areas of cerebellum.
The specific aims of this project are to 1a) complete a full neuropathologic analysis of ND2:SmoA1 medulloblastomas, 1b) determine by magnetic resonance imaging the limit of detection and rate of growth of ND2:SmoA1 mouse medulloblastoma, 2a) determine whether Nmyc is necessary for the sonic hedgehog component of mouse medulloblastoma development, 2b) determine whether Nmyc is sufficient to induce medulloblastomas in the absence of other shh target induction, 3a) determine whether Hes5 activation by notch2 is necessary for ND2:SmoA1 medulloblastoma and 3b) determine whether transgenic expression of constitutively active notch in GNPs is sufficient to generate medulloblastomas or whether it increases tumor incidence in ND2:SmoA1 or ND2:Nmyc mice when bred onto these backgrounds. The significance of this proposed work is that it will identify the essential elements of sonic hedgehog and notch pathway signaling required for medulloblastoma genesis and provide genetically precise models for testing and prioritizing candidate pathway inhibitors prior to human trials.
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