dactolisib and Medulloblastoma

Topics: Animals; Antineoplastic Agents; Apoptosis; Azepines; Cell Cycle; Cell Proliferation; Cerebellar Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Medulloblastoma; Mice; Mice, Inbred NOD; Mice, SCID; Protein Biosynthesis; Proto-Oncogene Proteins c-myc; Quinolines; TOR Serine-Threonine Kinases; Triazoles; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Medulloblastoma (MB) is the most common malignant brain tumor in children. Patients whose tumors exhibit overexpression or amplification of the MYC oncogene (c-MYC) usually have an extremely poor prognosis, but there are no animal models of this subtype of the disease. Here, we show that cerebellar stem cells expressing Myc and mutant Trp53 (p53) generate aggressive tumors following orthotopic transplantation. These tumors consist of large, pleiomorphic cells and resemble human MYC-driven MB at a molecular level. Notably, antagonists of PI3K/mTOR signaling, but not Hedgehog signaling, inhibit growth of tumor cells. These findings suggest that cerebellar stem cells can give rise to MYC-driven MB and identify a novel model that can be used to test therapies for this devastating disease.

Topics: Aminopyridines; Animals; Cell Proliferation; Cell Transformation, Neoplastic; Cerebellar Neoplasms; Cerebellum; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Genes, p53; Imidazoles; Medulloblastoma; Mice; Morpholines; Neural Stem Cells; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-myc; Quinolines; TOR Serine-Threonine Kinases