GW4 BioMed MRC DTP PhD Studentship: Targeting the Ubiquitin-Proteasome System in Glioblastoma

This project is one of a number that are in competition for funding from the ‘GW4 BioMed MRC Doctoral Training Partnership’ which is offering up to 19 studentships for 2018. The DTP brings together the Universities of Bath, Bristol, Cardiff and Exeter to develop the next generation of biomedical researchers.

Significance.

Glioblastoma GBM is the most common type of brain tumour in adults, representing 15.4% of all primary brain tumours. GBM has a poor overall survival rate of less than 10% after 5 years and this, and the lack of advancement in treatment options in the last decade, make the discovery and development of novel therapies a priority. By combining the expertise available within GW4Cancer in basic and translational GBM research, we are in a unique position to discover and validate novel drug targets for GBM, which could rapidly benefit brain tumour patients.

Originality.

The role for altered metabolism in cancer cells growth was first proposed by Otto Warburg over 70 years ago. Recent discoveries have now firmly established that altered metabolism fuels GBM growth and aggressiveness. We have found that the expression of a novel E3 ubiquitin ligase involved in protein degradation is upregulated in GBM that this enzyme is important for cell growth and proliferation, and using proteomics we have shown that it interacts with and potentially regulates metabolic proteins. We therefore propose that upregulation of this E3 ubiquitin ligase in GBM leads to the rewiring of GBM’s metabolic state into one permissive for malignant transformation.

Research training/added-value.

The successful student will work as part of a multidisciplinary team of scientists with strong expertise in both basic and translational cancer research. In particular, the student will gain in vivo skills which have been identified by the MRC as a strategic skill “vital to the development of safe and effective medicine”.

The work will be carried out in the Licchesi lab (Bath) which made the original observations and which has expertise in studying protein ubiquitylation. The Smalley and Siebzehnrubl labs (Cardiff) will provide access, expert knowledge and training on the use of in vivo models to study GBM tumourigenesis. The Brain Tumour Bank South West directed by Dr Kathreena Kurian (Bristol) will provide access to fully consented specimen with clinical follow up as well as training in translational GBM research. The project will benefit from on-going collaboration with chemical biologists (Dr Virdee, MRC-PPU, Dundee), proteomics expert (Prof Kessler, Oxford University) and cancer biology expert (Dr Bienz, MRC-Laboratory of Molecular Biology, Cambridge). We also have on-going collaboration with UbiQ (Amsterdam), a company which develop and commercialises ubiquitin research tools.

Knowledge transfer.

Following validation of the E3 ubiquitin ligase as a novel therapeutic target for GBM, we will then aim to initiate drug discovery programmes in collaboration with the Oxford Structural Genomics Consortium and MRC-Technology. This will accelerate the discovery and further development of drugs which could inhibit the enzymatic activity of the E3 ligase and thereby decrease GBM cell growth and proliferation.

IMPORTANT: In order to apply for this project, you should apply using the DTP’s online application form. More information on the application process may be found here: http://www.gw4biomed.ac.uk/projects-2/for-students/

APPLICATIONS OPEN ON 25 SEPTEMBER AND CLOSE AT 17:00 ON 24 NOVEMBER 2017.

You do NOT need to apply to the University of Bath at this stage – only those applicants who are successful in obtaining an offer of funding from the DTP will be required to submit an application to study at Bath.