Glioblastoma (GBM) is the most common aggressive primary brain tumour, with a very poor prognosis and no effective therapy, accounting for more than 190,000 deaths worldwide per year. The high degree of intra-tumoural heterogeneity has been identified as a major cause of treatment failure. It is therefore imperative to replicate intra-tumoural heterogeneity in models studying tumour biology and in drug discovery and development programmes.
There currently exist no GBM models that adequately cover all aspects of tumour biology. Genetically engineered mouse models display limited tumour heterogeneity, compromising their clinical relevance. Although patient-derived xenograft mouse models are the gold standard, they are technically demanding, require immunosuppression, critically lack microenvironmental immune-cell components, and are not amenable to medium-high throughput screening. Most importantly they also do not replicate tumour heterogeneity.
We have developed a culture technology that allows the culture of human epileptic cortical and hippocampal tissue in 3D for up to 8 weeks in vitro (OrganDot®). Using this technology, we have preliminary data showing that fresh GBM tissue can be grown for 8 weeks in vitro GliomaOrganDots(GODots). These cultures preserve many of the cellular features of GBMs and importantly here, uniquely allow the possibility of generating single 3D cultures from cells derived from multiple tumour sites, offering the potential to generate cultures that each replicate he genomic heterogeneity of the entire tumour.
This project will characterise and optimise protocols for generating single tumour site and pan-tumour GODots and determine their utility to screen novel compounds and predict therapy responsiveness. Our industrial collaborator, Asterand owns the core IP and could rapidly commercialise GODots as a screening tool for GBM research. If successful the model holds huge potential for capturing heterogeneity across many solid tumours.
Principal investigatorProfessor William Gray
Co-InvestigatorDr Florian Siebzehnrubl
Professor Mark Gumbleton