PDTB-24. TARGETED THERAPY FOR LEPTOMENINGEAL METASTASIS OF MEDULLOBLASTOMA

Abstract

Medulloblastoma (MB) is the most common malignant pediatric brain tumor that arises from the cerebellum. MB can disseminate through the cerebrospinal fluid to the leptomeninges covering the brain and spinal cord. Leptomeningeal metastasis, a frequent finding at diagnosis and recurrence, is associated with poor prognosis. Transcription factor Atonal Homolog 1 (ATOH1) plays a crucial role in cerebellum morphogenesis and the development of MB driven by aberrant Sonic Hedgehog/Patched (SHH/PTCH) signaling. Dysregulated ATOH1 expression is also associated with primary and recurrent SHH MBs. We generated several transgenic mouse lines with conditional Atoh1 expression, which were subsequently bred to Ptch1+/- mice that exhibit increased SHH signaling. Approximately 30% of Ptch1+/- mice develop MBs; however, Ptch1+/- animals with Atoh1 transgene expression all develop highly penetrant MBs with extensive leptomeningeal metastasis, a pattern identical to a xenograft model of human SHH MB. Non-invasive detection methods using bioluminescence assays and magnetic resonance imaging revealed primary tumors and metastatic tumors in the spinal cord of these animals. Comparative lineage studies also indicate metastatic tumor arises from primary tumor in the cerebellum. Similar to human MBs which maintain the SHH signature during metastasis and recurrence, metastatic tumors retain abnormal SHH signaling and Atoh1 expression. Gene expression profiling of metastatic tumors revealed significant enrichment for cytoskeletal and extracellular matrix networks, consistent with adaptation of metastatic tumor cells to an active migration and new microenvironment. Treatment with bone morphogenetic protein (BMP) or cyclopamine, a SHH antagonist, significantly suppressed the proliferation of tumor cells. Moreover, a 2-week treatment with vismodegib, a clinically approved SHH pathway inhibitor, is sufficient to almost completely wipe out metastatic MBs. Our studies reveal an important role for Atoh1 in MB metastasis. The efficacy of targeted therapy for metastatic MBs demonstrates the utility of this animal model for understanding mechanisms of metastasis and evaluating potential therapeutics.