PhD studentship - Investigating the metabolism of brain tumours using hyperpolarized magnetic resonance imaging. The Cancer Research UK Cambridge Institute (CRUK CI) is a joint venture between the Charity, Cancer Research UK, and the University of Cambridge. The Institute has excellent state-of-the-art facilities and research ranges from basic cancer biology and computational biology through to translational research and clinical application. Graduate students play a pivotal role in the continuing success of our research programmes and gaining a studentship in the Institute is an excellent opportunity to start a research career in an environment committed to training outstanding cancer research scientists of the future. Professor Kevin Brindle, Head of the Molecular Imaging of Cancer group, wishes to appoint a student to work on the project entitled: Investigating the metabolism of brain tumours using hyperpolarized magnetic resonance imaging. Project details Patients with similar tumour types can show markedly different responses to the same therapy. The development of new treatments would benefit, therefore, from the introduction of imaging methods that allow an early assessment of treatment response in individual patients, allowing rapid selection of the most effective treatment [1]. For over 10 years, members of the Brindle lab have been developing methods for detecting the early responses of tumours to therapy, including magnetic resonance (MR) imaging of tumour cell metabolism using hyperpolarized 13C-labelled cell metabolites. See 'Further information' below. More recently, they have investigated glycolytic metabolism in patient derived xenograft (PDX) models of glioblastoma. These measurements have shown considerable heterogeneity between tumours derived from different patients, which we have evidence is related to underlying oncogenic mutations. Earlier this year we conducted our first study in a patient using this technique (the first outside North America) and will shortly conduct further studies in glioblastoma patients. The aim of this studentship is to use these PDX models to understand the factors responsible for this heterogeneity and then to use this information to gain a greater understanding of what the clinical imaging is telling us about an individual patient's tumour. Our hypothesis is that these images will have prognostic value and may also predict treatment outcome. The student will learn a variety of techniques, including magnetic resonance imaging and spectroscopy; metabolic biochemistry, particularly as it relates to oncology and tumour cell and molecular biology. For up to date information about the research group, including their most recent publications, please see their website at: http://www.cruk.cam.ac.uk/research-groups/brindle-group Preferred skills/knowledge Applicants should have excellent communication and team working skills with a degree in the physical or biomedical sciences. A Masters degree is not essential but some laboratory experience would be beneficial. Funding This project is funded by a Cancer Research UK studentship that includes full funding for University and College fees and a stipend of £19,000 per annum. Eligibility No nationality restrictions apply to Cancer Research UK funded studentships. Applications are invited from recent graduates or final year undergraduates who hold or expect to gain a first/upper second class degree (or equivalent) in a relevant subject from any recognised university worldwide. How to apply Please send your academic CV and a covering letter as attachments to kmb1001@cam.ac.uk Your CV should include a list of the examinations taken at undergraduate level and if possible, your examination results. Also the names and contact details of two academic referees who have agreed to act on your behalf.

Your covering letter should explain why you wish to be considered for the studentship and which qualities and experience you will bring to the role. Please also state how you learned of the studentship. Deadline The closing date for applications is 30 November 2016. Further information The Brindle lab has been developing methods for detecting the early responses of tumours to therapy, including magnetic resonance (MR) imaging of tumour cell metabolism using hyperpolarized 13C-labelled cell metabolites. Nuclear spin hyperpolarization can increase sensitivity in the MR experiment by >10,000x. This has allowed us to image the location of labelled cell substrates in vivo and, more importantly, their metabolic conversion into other metabolites. These substrates include pyruvate [2], lactate [3], glutamine [4], glutamate [5], fumarate [6], bicarbonate [7] and ascorbate [8] and glucose [9]. Reviewed in [10]. Exchange of hyperpolarized 13C label between lactate and pyruvate can be imaged in models of lymphoma and glioma and this flux is decreased post-treatment [2,11]. Hyperpolarized [1,4-13C]fumarate can be used to detect tumour cell necrosis post treatment in lymphoma [6] and both the polarized pyruvate and fumarate experiments detected early evidence of treatment response in a breast tumour model [12] and also early responses to anti-vascular [13] and anti-angiogenic drugs [14]. Tissue pH can be imaged from the ratio of the signal intensities of hyperpolarized H13CO3¯ and 13CO2 following intravenous injection of hyperpolarized H13CO3¯ [7] and tumour redox state can be determined by monitoring the oxidation and reduction of [1-13C]ascorbate and [1-13C]dehydroascorbate respectively [8]. Tumour glycolysis can be monitored by measuring the conversion of hyperpolarized [U-2H, U-13C]glucose to lactate and this flux was shown to decrease post-treatment [9]. More recently we have shown that we can follow, using hyperpolarized [1-13C]pyruvate, the progression of pancreatic precursor lesions, in a genetically engineered mouse model of the disease, which potentially could be used clinically to guide earlier intervention [15]. References 1. Brindle, K., Nature Rev Cancer, 8, 94-107 (2008) 2. Day, S.E., et al., Nature Med, 13, 1382-1387 (2007) 3. Kennedy, B.W.C., et al., J Am Chem Soc, 134, 4969−4977 (2012) 4. Gallagher, F., et al., Magn. Reson. Med., 60, 253-257 (2008) 5. Gallagher, F., et al., Magn Reson Med, 66, 18-23 (2011) 6. Gallagher, F.A., et al., Proc Natl Acad Sci U S A, 106, 19801-19806 (2009) 7. Gallagher, F., et al., Nature, 453, 940-943 (2008) 8. Bohndiek, S.E., et al., J Am Chem Soc, 133, 11795-11801 (2011) 9. Rodrigues, T.B., et al., Nat Med, 20, 93-97 (2014) 10. Brindle, K.M., J. Amer. Chem. Soc., 137, 6418-6427 (2015) 11. Day, S.E., et al., Magn Reson Med, 65, 557-563 (2011) 12. Witney, T.H., et al., Brit. J. Cancer, 103, 1400-1406 (2010) 13. Bohndiek, S.E., et al., Molecular Cancer Therapeutics, 9, 3278-3288 (2010) 14. Bohndiek, S.E., et al., Cancer Research, 72, 854-864 (2012) 15. Serrao, E.M., et al., Gut, 65, 465–475 (2016) Please quote reference SW10294 on your application and in any correspondence about this vacancy. The University values diversity and is committed to equality of opportunity. The University has a responsibility to ensure that all employees are eligible to live and work in the UK.