MEDU-10. THERAPEUTIC TARGETING OF STEM CELL SELF-RENEWAL IN CHILDHOOD MEDULLOBLASTOMA: STRATEGIES FOR BLOCKING RECURRENCE

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Group 3 MB patients face the highest incidence of metastasis and poor overall survival. The early onset and aggressive nature of MB suggest a stem cell origin, where a highly self-renewing transformed cell of the postnatal cerebellum drives MB tumorigenesis. In this work, we explore the therapeutic value of activating WNT signaling and targeting other essential drivers of self-renewal, BMI1 and MSI1. A small molecule BMI1 inhibitor, PTC-028, induced a remarkable decrease in self-renewal, while reducing local and spinal metastatic disease in recurrent MB, which is striking as no prior drug has shown efficacy against recurrent Group 3 MB. Although mouse and human neural stem cells (NSCs) express BMI1 and are mildly sensitive to BMI1 inhibitors, no significant toxicity was observed in NSCs upon PTC-028 treatment, at doses that effectively kill MB cells. Another novel therapeutic paradigm includes activating Wnt signaling in otherwise non-Wnt MB, which abrogates self-renewal and tumorigenicity of these aggressive tumors. For safe and non-toxic activation of Wnt in preclinical models, we identified L807mts, a novel inhibitor that functions through a substrate-to-inhibitor conversion mechanism within the catalytic site of GSK. A final therapeutic strategy lies in the discovery of the targetable MB-specific interactome of the RNA binding protein (RBP) Musashi1. shRNA knockdown of Msi1 decreased the self-renewal capacity of MB stem cells, significantly decreased tumor burden and increased survival in our PDX model. Comparative eCLIP (enhanced cross-linking and immunoprecipitation) of MB stem cells and normal NSCs, combined with mass spectrometry and RNA-sequencing of shMSI1 MB cells has elucidated novel therapeutic targets in interactome of MSI1. Characterization and therapeutic targeting of self-renewal mechanisms may provide an opportunity to limit treatment-resistant stem cell populations from driving patient relapse in Group 3 MB, a disease currently lacking any targeted therapies.