Project description
Glioblastoma (GBM) is the most aggressive and treatment-resistant form of brain cancer, with a median survival of less than 15 months despite standard-of-care interventions such as surgery, radiotherapy, and temozolomide (TMZ). Recurrence is nearly universal, driven by intrinsic tumour resistance and a profoundly immunosuppressive tumour microenvironment (TME). There is a critical need for novel therapeutic strategies that target both tumour-intrinsic mechanisms and immune evasion.
Our recent research has identified guanylate-binding proteins (GBPs) – a family of interferon-inducible GTPases – as key regulators of GBM progression and immune suppression. We have shown that GBPs are overexpressed in GBM and associated with poor prognosis. Notably, GBPs also contribute to TMZ resistance. GBPs are also enriched in tumour-associated macrophages (TAMs), where they help maintain an immunosuppressive microenvironment. Genetic deletion of GBPs in either GBM cells or TAMs reduces tumour growth and extends survival in preclinical models, highlighting their potential as dual-function therapeutic targets.
This project will:
1. Investigate the role of GBPs in tumour growth and drug resistance using CRISPR/Cas9-mediated gene inactivation;
2. Elucidate the impact of GBPs on the immune microenvironment using GBP knockout mouse models and single-cell RNA sequencing to analyse TAM polarisation and T cell dynamics.
This research has the potential to transform GBM treatment by identifying novel therapeutic targets that simultaneously suppress tumour growth and modulate the immune response. By sensitising tumours to immunotherapy, it could pave the way for more effective combination treatments in a cancer type with currently limited options.
