PS1 - 169 Discovering the Treatment Refractory BTIC Population in Group 3 Medulloblastoma through Therapy Adapted Patient-Derived Human Mouse Xenograft (PDX) Model. (18th October 2016)

• Record Type: Journal Article
• Authors: Bakhshinyan, D.; Vijayakumar, T.; Manoranjan, B.; McFarlane, N.; Venugopal, C.; Singh, M.; Qazi, M.; Vora, P.; Singh, S.
• Is Part Of: Canadian journal of neurological sciences. Volume 43(2016)Supplement 4
• Page Start: S10
• Page End: S10
• Publication Date: 2016-10-18
• Subjects: Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Electronic journals; 616.8
• DOI: 10.1017/cjn.2016.357
• Languages: English
• ISSNs: 0317-1671

Abstract

Abstract : Medulloblastoma (MB), the most common malignant pediatric brain tumor, is categorized into four molecular subgroups. Given the high rate of metastatic dissemination at diagnosis and recurrence in Group 3 MBs, these patients have the worst clinical outcome with a 5-year survivorship of approximately 50%. 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 tumour initiating cells we aim to identify and characterize the treatment-refractory cell population in Group 3 MBs. Mice were sacrificed at multiple time points during the course of tumor development and therapy: (i) at engraftment; (ii) post-radiation; (iii) post-radiation and chemotherapy; and (iv) at MB recurrence. MB cell populations recovered separately from brains and spines were comprehensively profiled for gene expression analysis, stem cell and molecular features to generate a global, comparative profile of MB cells through therapy. We report a higher expression of CD133, Sox2 and Bmi1 in addition to increased self-renewal capacity following chemoradiotherapy treatment. The enrichment map constructed from global gene expression analysis showed an increase in pathways regulating self-renewal, DNA repair and chemoresistance post-therapy despite the apparent decrease in tumour size and vascularity. Additionally, from gene expression at MB recurrence, we identified a list of genes that negatively correlate with survival in patients diagnosed with Group 3 MB. A differential genomic profile of the "treatment-responsive" tumors against those that fail therapy may contribute to discovery of novel therapeutic approaches for the most aggressive subgroup of MB.