This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Medulloblastoma is the most common childhood brain tumor and is of broad scientific interest because tumors are essentially overgrowths of perinatal neuronal stem cells of the cerebellum. Two-thirds of medulloblastomas are characterized as the classic-histology subtype. However, irrespective of histological subtype, nearly all children with medulloblastoma are treated with surgery, chemotherapy, and craniospinal irradiation (CSI) under the assumption that leptomeningeal metastases are present. CSI becomes especially problematic in children under three years of age, for whom CSI results in severe cognitive impairment results. Unfortunately, in this young population treatment with surgery plus chemotherapy (but not CSI) has only a 34% progression-free survival rate for classical histology medulloblastoma. This low progression-free survival rate clearly indicates the need for better radiation-sparing treatments in younger patients. Therapies targeted at key signal transduction molecules might one day overcome both mortality and treatment-related morbidity of current regimens. Physiologically accurate, transgenic preclinical models can have an important role in the development of such new therapies. This project addresses the biochemical underpinnings of medulloblastoma through a genetically engineered mouse model (GEM), developed by the Keller laboratory. The model relies on concurrent conditional deletion of one copy of the Patched1 (Ptc1) receptor for Sonic Hedgehog (Shh) as well as the p53 gene in the juvenile cerebellum. These Pax7Cre,Patched1 mice develop brain tumors with 100% penetrance by 90 days of age. Tumors in this model are similar to the most common clinical presentation: classic histology, uniform local invasion, and frequent leptomeningeal metastasis. The Keller laboratory has shown that bortezomib (velcade, PS-341), a 26S proteasome inhibitor, had significant anti-tumor activity in medulloblastoma, which was accompanied by restoration of Ptc1 protein and downregulation of the hedgehog-signaling pathway. The goal of this project is to further define the therapeutic effect and mechanism of bortezomib in medulloblastoma. The strategy is to study the shape of the cerebellum in the developing wild-type mouse and to make comparisons with treated and untreated tumor-prone mutants.
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