RM-06IN VITRO CLONAL EVOLUTION OF GLIOBLASTOMA (GBM) BRAIN TUMOUR INITIATING CELLS (BTIC) TO MODEL TUMOUR RECURRENCE

Glioblastoma (GBM) is the most common and highly aggressive primary adult brain tumour. Despite multimodal therapy, patients on average experience relapse at 9 months and median survival rarely extends beyond 15 months. Targeting the cells that drive GBM formation as well as its inevitable and rapid recurrence has remained a major challenge, likely due to intra-tumoral heterogeneity. At the genetic level, this heterogeneity has prompted a molecular classification of GBM based on differential transcriptome profiling by TCGA. At the cellular level, this heterogeneity may be explained by the existence of multiple subpopulations of cancer cells that have acquired stem cell properties, termed brain tumour initiating cells (BTICs). We postulate that different BTIC subpopulations are capable of first initiating the tumor, and later evading therapy to seed the tumor relapse or recurrence, as they undergo clonal evolution over time in response to various environmental cues including chemotherapy and radiotherapy. In this study, we developed a novel in vitro BTIC model to profile the clonal evolution of treatment naïve GBM BTICs through therapy (temozolomide and radiation treatment) based on transcriptome analysis, stem cell assays and BTIC protein marker expression (CD133, CD15, Sox2 and Bmi1). The expression profile of in vitro treated GBM was compared to recurrent GBM patient samples to determine if our model recapitulated clonal BTIC evolution as seen in patients. Profiling the dynamic nature of BTICs and their evolution over the course of treatment and tumour progression may offer novel therapeutic targets for the treatment of primary and recurrent GBM.