Glioblastoma (GBM) is the commonest primary malignant brain tumour. Treatment involves surgery, radiotherapy and chemotherapy, but outcomes remain very poor. In the past 5-10 years, there have been several failed phase III trials of targeted therapies. The reasons for the lack of progress are multifactorial but includes the challenges of delivering drugs across the blood-brain barrier (BBB) / blood-brain tumour barrier (BBTB). GBM tumours alter the vasculature, and this altered barrier is known as the BBTB.
Current in vitro models of the BBTB are limited with very restricted relevance so rodent xenograft models for GBM/BBTB research are the go-to method for investigating drug delivery and efficacy, and basic biology of the BBTB. Novel drugs that work on GBM xenograft models have not been successful in the clinic. This suggests that the current xenograft models do not represent the human disease, in particular the BBTB. Our collaborators at the Open University have recently established a novel BBB model based on deriving brain-like endothelial cells (BECs) from iPSCs and co-culturing with astrocytes on a hydrogel.
The objective of this PhD studentship is to establish and biologically validate a novel in vitro model of the BBTB by inclusion of GBM cells with the BBB model. Our collaborator at University of Edinburgh has provided several well-defined cell lines for this, including neural stem cells (NSCs) and patient derived GBM stem-like cells (GSCs). The inclusion of the GBM cells enables the establishment of an in vitro BBTB and a way to study the effects of the GBM cells on the BECs in comparison to the normal BBB with control NSCs. Barrier tightness, astrocyte endfeet, gene expression, drug crossing and tight junction protein expression will be assessed. Finally, using transcriptomics, the novel in vitro BBTB model will be compared to GBM patient datasets of the BBTB to define the biological relevance of the in vitro model to the human disease. This is a key step in the validation of the model.
The impact of this model will be to reduce animal usage significantly and in the longer-term have the potential to replace GBM xenograft models for testing of novel GBM therapeutics. This could in the long run increase translational to the human disease and ultimately improve outcomes for GBM patients.
Applicants with extensive experience in cell culture and cell biology techniques with knowledge of GBM biology and/or BBB are encouraged to apply. A minimum of a 2:1 in a relevant BSc degree is a requirement. Email Dr David Dickens ([Email Address Removed]) for any further details and to apply.