Current clinical trials for recurrent medulloblastoma (MB) patients who no longer respond to risk-adapted therapy are based on genomic profiles of primary, treatment-naïve tumors. These approaches will provide limited clinical benefit for patients since recurrent metastatic MBs are highly genetically divergent from their primary tumor. Treatment for MB patients who present with recurrent metastatic lesions is limited to palliative care, and the development of novel therapeutics for these patients is encumbered by rare clinical opportunities in which specimens may be obtained from relapsed patients. Consequently, we have adapted the existing COG (Children’s Oncology Group) Protocol ACNS0332, for children with newly diagnosed high-risk MB, for treatment of NOD-SCID mice engrafted with human MB xenografts. Our novel patient-derived xenograft models capture clonal evolution of MB cell populations in response to therapy, allowing for comprehensive, serial profiling of tumor clones by regular time point sampling of tumors throughout the course of our mouse-adapted therapy. Our experimental approach defines several tractable targets, including the epigenetic regulator Bmi1 and strategic Wnt activation, which mitigate recurrent MB. As future clinical oncology trials will most likely begin with relapsed patients, therapeutic targets from comparative analyses in primary and matched-recurrent tumors offer the greatest clinical yield and may be readily translated to the patient bedside.