PhD studentship available at the University of Cambridge, UK (Kevin Brindle Lab):
Monitoring tumour responses to treatment using hyperpolarized magnetic resonance imaging
Kevin M. Brindle
Department of Biochemistry, University of Cambridge
Tennis Court Road, Cambridge CB2 1GA
and
Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre,
Robinson Way, Cambridge, CB2 0RE
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].
We 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 cellular 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]. 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 [2,10]. 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 can detect early evidence of treatment response in a breast tumour model [11] and also early responses to anti-vascular [12] and anti-angiogenic drugs [13]. 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].
We have recently obtained funding for clinical trials with polarised pyruvate and fumarate to detect treatment response in lymphoma, glioma and breast cancer patients.
The aim of this studentship is to further develop this technique. This will include investigation of other cell substrates and other ways in which the technique can be used to monitor tumour progression and response to treatment. The student will learn a variety of techniques, including magnetic resonance imaging and spectroscopy; metabolic biochemistry, particularly as it relates to oncology; tumour cell biology and molecular biology.
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. Day, S.E., et al., Magn Reson Med, 65, 557-563 (2011)
11. Witney, T.H., et al., Brit. J. Cancer, 103, 1400-1406 (2010)
12. Bohndiek, S.E., et al., Molecular Cancer Therapeutics, 9, 3278-3288 (2010)
13. Bohndiek, S.E., et al., Cancer Research, 72, 854-864 (2012)
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Tiago B. Rodrigues, PhD
Phone: +44 (0) 1223 769724
Fax: +44 (0) 1223 769510
E-mail: Tiago.Rodrigues@cruk.cam.ac.uk
CRUK Cambridge Institute,
University of Cambridge,
Li Ka Shing Centre,
Robinson Way,
Cambridge CB2 0RE
United Kingdom
http://www.cambridgecancer.org.uk/
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