DEfiNING SPATIAL HETEROGENEITY OF A NOVEL LIVING BIOBANK OF POST-SURGICAL RESIDUAL GLIOBLASTOMA TO DEVELOP STRATEGIES FOR TARGETED THERAPY

Abstract

Abstract AIMS Glioblastoma is the most common cancer arising within the brain accounting for >2,000 deaths/year in the UK. Current standard-of-care therapy consists of maximal safe surgical resection followed by radiochemotherapy which activates the cellular DNA damage response (DDR). However, disease prognosis remains poor (median OS ~12-15 months). This stagnation in the development and clinical translation of novel therapeutics is largely attributed to extensive inter- and intra-tumoral heterogeneity and resistant glioma stem cell (GSC) niches. Traditionally, primary ex vivo and in vivo models of glioblastoma have been generated from the resected tumour mass potentially omitting the post-surgical residual tumour cells that give rise to disease recurrence and morbidity. METHOD Multiple parallel primary ex vivo GSC cell models were generated from anatomically discrete regions of en-bloc partial lobectomy glioblastoma specimens to produce 3D models of resected (tumour “core”) and typically residual (distal invasive tumour “edge”) GSC niches. These models were characterised using an array of biomolecular techniques and 3D based assays. RESULTS Preliminary RNA-seq analyses revealed largely divergent transcriptional landscapes for resected vs residual GSCs and protein expression/immunofluorescence analyses also identified key differences in GSC and DDR ex- pression, and subsequent cellular responses to current standard-of-care radio-chemotherapy regimens. CONCLUSIONS These data reveal phenotypic relationships between GSC “stemness” and DDR activity, therefore highlighting the potential clinical relevance of our novel parallel resected and residual ex vivo glioblastoma models. Characterisation of further models from within our 3D GSC biobank will also aid evaluation of novel therapeutics capable of targeting post-surgical GSC subpopulations leading to improved disease outcomes.