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Targeting hypoxic gliomas through their mitochondrial metabolic network


Project Description

Applications are invited for a 3-year fully-funded PhD studentship starting in October 2019, supervised jointly by Dr Daniel Tennant and Professor Colin Watts.

The presence of hypoxic (low oxygen) regions in tumours and the effect of this on therapeutic response was first reported 60 years ago. There is now direct evidence showing that hypoxia drives malignant tumour phenotypes including resistance to therapy, increased metastatic spread and immunosuppression. Importantly, it has been suggested that over 50% of solid tumours contain hypoxic areas, making it both a significant clinical issue and a highly attractive area for drug targeting.

There are a large number of cancers in which novel hypoxia-targeting agents could have a profound effect on patient outcomes. One tumour type in which hypoxia is a particular clinical challenge is glioblastoma. These are highly malignant brain tumours characterised by extensive areas of necrosis and hypoxia. They are particularly therapy-resistant; patients have a 2-year survival of less than 30% with gold-standard treatment (concomitant radiotherapy and temozolomide). Agents that target tumour hypoxia could make a profound difference to overall survival in patients with glioblastoma, yet drugs targeting these pathways have not reached the clinic, often due to unacceptable off-target effects. Better approaches to targeting tumour hypoxia are clearly required.

When oxygen availability is restricted, malignant cells rely on alternative oxygen-independent pathways to produce metabolites required for survival, cell repair and oncogene-induced proliferative drive. This hypoxia-induced remodelling of the metabolic network often leads to reduced redundancy so that specific metabolic pathways become essential for viability or proliferation in hypoxic conditions, providing a therapeutic window that can be exploited.

The mitochondria lie at the heart of central carbon metabolism, yet little is known about how some key metabolites are trafficked between the cytosol and the mitochondrial matrix, and how this is affected by oxygen tension. This project will therefore investigate the function of specific transporters predicted to be essential in hypoxia, with the express purpose of identifying those that are selectively essential in these conditions. It will utilise techniques including CRISPR/Cas9-mediated knockout, hypoxic cell culture, primary cell isolation, stable isotope metabolic tracing and in vivo tumour studies.

Person Specification
Applicants should have a strong background in biochemistry. They should have a commitment to cancer research and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in biochemistry or a relevant subject.

How to apply

Informal enquiries should be directed to Dr Daniel Tennant ()

To be considered for this studentship, please send the following documents to Viktorija Ziabliceva ():

• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.

Funding Notes

British and EU nationality applicants are eligible for both the cost of tuition fees and a yearly stipend over the course of the PhD programme.

References

Hollinshead et al. (2018) Cell Reports 22, 3107-3114
Eales et al. (2016) Oncogenesis 5, e190
Tennant et al. (2010) Nature Rev Cancer 10, 267-77

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