MEDU-25. GENES PRESERVING STEM CELL STATE IN GROUP 3 MB BTICs CONTRIBUTE TO THERAPY EVASION AND RELAPSE

Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Out of all the subgroups, Group 3 patients face the highest incidence of leptomeningeal spread and overall patient survival of less than 50%. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naïve tumors, provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumors. By adapting the existing COG (Children’s Oncology Group) Protocol for children with newly diagnosed high-risk MB for treatment of immuno-deficient mice intracranially engrafted with human MB brain tumor initiating cells (BTICs), we have characterized the rare treatment-refractory cell population in Group 3 MBs. MB cell populations recovered separately from brains and spines during the course of tumor development and therapy were comprehensively profiled for gene expression analysis, stem cell and molecular features to generate a global, comparative profile of MB cells through therapy to relapse. One of the most intriguing observations from our gene expression data was consistent over-expression of proteins belonging to Inhibitor of DNA-binding/differentiation (ID) family and a longevity associated protein bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) in our refractory population. shRNA-mediated knockdown of BPIFB4 led to markedly decreased self-renewal and proliferation of MB cells, as well as extended survival and reduced tumour burden in vivo. Furthermore, a small molecule inhibitor targeting endothelial nitric oxide synthase (eNOS), a downstream substrate of BPIFB4, impeded the growth of several MB patient-derived lines at low nanomolar concentrations. For the first time, we describe the role of BPIFB4 as a potent regulator of self-renewal and specific driver of medulloblastoma relapse. Our differential genomic and gene expression profiles of the “treatment-responsive” tumors against those that fail therapy will thus contribute to discovery of novel therapeutic targets for the most aggressive subgroup of MB.