MBRS-05. A p53 INDEPENDENT MOUSE MODEL OF GROUP 3 MEDULLOBLASTOMA

Group 3 medulloblastoma (MB) has been characterized with MYC amplification or overexpression. However, the function of MYC in tumor initiation and progression has not been well studied. A few years ago, two groups demonstrated that Group 3 MB can be generated from cerebellar stem cells with overexpression of MYC and mutant p53. However, this tumor may not faithfully recapitulate human tumors because mutation or deletion of p53 is rarely detected in human Group 3 MB at diagnosis. In our recent studies, we found that MYC alone is sufficient to transform granule neuron progenitors (Math1+) and Bergmann glia (Sox2+) in the neonatal cerebellum. Comprehensive gene expression analysis shows that these tumors faithfully resemble Group 3 MB. Moreover, the tumors generated from Math1+ and Sox2+ cells represent two distinct subtypes of Group 3 MB. Thus, these models are valuable tools to study tumor biology and test novel therapies. We identified that lactate dehydrogenase A (LDH-A), which contributes to the conversion of pyruvate to lactate during energy metabolism, is overexpressed in both mouse and human tumors and highly correlated with MYC expression levels. These observations indicate that targeting LDH-A may represent a new therapeutic avenue to treat this disease. We will use our new murine models and human xenografts to determine whether inhibition of LDH-A prevents tumor growth. If successful, this approach could be translated for the development of new anti-cancer therapies for Group 3 MB, with preferential killing of cancer cells without significant toxicity to normal cells.