Isocitrate dehydrogenase wild-type (IDHwt) glioblastoma (GBM) is the most frequent and aggressive adult brain tumour. 85% of patients die within two years despite aggressive treatment (surgical resection and adjuvant chemo-radiotherapy). The elucidation of disease subtypes based on tumour mutational profiling, gene expression and DNA methylation has so far failed to translate into improved clinical outcomes. Furthermore, immunotherapy has been ineffective in clinical trials in GBM to date.
The GBM tumour microenvironment (TME) consists of heterogeneous non-neoplastic cells, including glial cells, microglia, immune cells, vascular cells, reactive astrocytes and endothelial cells, in addition to various GBM cell subpopulations such as stem cells. These cell populations exist in several niches and have varying interactions with heterogeneous tumour cells. We believe that GBM TME-specific subtypes may provide directions for better precision therapy, having particular utility to identify patients that may be candidates for immunotherapy.
To this end, in the recently concluded EC-funded ‘GLIOTRAIN’ project (www.gliotrain.eu) we established a novel subtyping approach for IDHwt GBM based for the first time on tumour microenvironment (TME) composition . In the current proposal, we will implement a multi-‘omics approach using pre-treatment IDHwt patient tumours who received standard of care Stupp protocol (radiotherapy plus concomitant, adjuvant temozolomide). We will perform integrative modelling of multi-‘omics data and other clinical covariates to unravel the underlying biology of the TME subtypes. This approach will uncover TME subtype specific targeted vulnerabilities and resistance mechanisms.
Finally, we will develop orthotopic syngeneic models representing TMELow, TMEMedium(Med) and TMEHigh tumours and will exploit these models to evaluate the impact of TME subtype specific immuno-combinatorial treatments.
Overall, we hope to identify novel ‘precision medicine’ subtype specific treatment approaches for future clinical development in GBM, and to generate sufficient data to support a post-project Phase 2 clinical trial.
