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Medulloblastoma is a highly malignant childhood brain tumor and is often characterized by alterations in cell cycle regulatory pathways and genes. Using FDA-approved arsenic trioxide (ATO) treated ND2-SmoAl mouse model, we present an integrated imaging and systems biology approach to assess tumor responses to ATO and to uncover the complexity of therapeutic molecular biology. Kaplan-Meier survival and MRI tumor growth analyses established the effectiveness of ATO treatment. Differential analysis of protein data identified biologically plausible gene markers. Differential dependence network analyses further revealed novel rewiring “hubs” of biological networks triggered by ATO at systems level. Functional analyses on statistically significant networked molecular markers confirmed ATO's role as an effective anti-proliferative and pro-apoptotic drug, in vivo.