Self-funded PhD opportunities
Mitochondrial biomarkers and drug development for personalised treatment of brain cancer
- Application end date: Applications accepted all year round
- Funding Availability: Self-funded PhD students only
- Department: School of Pharmacy and Biomedical Sciences
- PhD Supervisor: Rhiannon McGeehan and Aikaterini Lalatsa
Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults and carries a dismal prognosis. Treatment is hampered by its unique biology, which includes differential cellular and patient response to existing therapies. Due to current treatments that target nuclear DNA being so ineffective, researchers are turning to alternative targets within the cell, such as the mitochondria.
Mitochondria are the energy-producing compartments inside cells, and mitochondrial alterations are a known hallmark of cancers. Mitochondria also have their own DNA (mtDNA). Although numerous mutations have been found in brain tumour mtDNAs [LloydNeuroOnc15; LloydIJMS16, submitted], their potential significance in terms of the development of new and better treatment options for GBM patients is only just coming to light.
Recently, we have discovered an inherited mtDNA mutation that is enriched in GBM-patients compared to healthy-subjects. The mutation occurs in an important inhibitor binding site within a mitochondrial enzyme that plays a key role in cellular energy production [LloydNeuroOnc15]. Significantly, the mutation seems to influence mitochondrial-targeted drug sensitivity (SongHumMut16; KeatleyPhDthesis16; KeatleyHumMut16, in prep). Additional preliminary data suggests that a further four mitochondrial factors also influence mitochondrial-targeted drug sensitivity.
This project is divided into 3 main research arms:
- Drug-sensitivity biomarker validation: in vitro using a large (20+) panel of GBM-biopsy derived cell lines (BTRC, UoP) and in vivo using a pre-clinical mouse model (Faculty of Medicine, Hammersmith Campus, Imperial College, London);
- Drug design and synthesis: of ~100 novel small molecule inhibitors designed specifically to target the mutant mitochondrial enzyme found in GBM-patients (Duquesne University, USA);
- Drug screening: high throughput screening of the inhibitors will be performed using our yeast model that has been genetically modified to contain the GBM-mutant mitochondrial enzyme (CNRS, France); the most promising candidates will then be tested in vitro on the panel of GBM cell lines mentioned above (BTRC, UoP).
The long-term goal of the project is to provide the clinician with a simple genetic test that they can use to inform the patient which treatment will be most effective. Together with the new drugs under development here, this project tackles the current gulf of ineffective treatments. If just one of the biomarkers or drugs under development here is successful (even if just partially), it has the potential to transform the current survival outcomes of GBM patients.
This multi-disciplinary project is a collaboration between the flagship Brain Tumour Research-funded research centre at the University of Portsmouth, and three other high impact research centres based in the UK, France and US and provides superb training opportunities for the candidate.
This PhD opportunity is available to self-funded students. Bench fees may apply. For more information please contact the project supervisor.
How to apply:
To apply or make an enquiry, please visit postgraduate research: Biomedical, Biomolecular and Pharmacy
All applications should use our standard application forms and follow the instructions given under the ‘Research Degrees’ heading on the following webpages: http://www.port.ac.uk/application-fees-and-funding/applying-postgraduate/#rd.
When applying please note the project code - PHBM3070217