Imaging tumour phenotype and underlying genotype using hyperpolarized magnetic resonance imaging

We have been developing magnetic resonance imaging (MRI) methods for interrogating 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 cell metabolites. These substrates include pyruvate, lactate, glutamine, glutamate, fumarate, bicarbonate, ascorbate and glucose. Reviewed in (1-3). Exchange of hyperpolarized 13C label between lactate and pyruvate has been imaged in various tumour models and this flux has generally been shown to decrease post-treatment and hyperpolarized [1,4-13C]fumarate has been shown to detect subsequent tumour cell necrosis. Tissue pH can be imaged from the ratio of the signal intensities of hyperpolarized H13CO3¯ and 13CO2 following intravenous injection of hyperpolarized H13CO3¯ and tumour redox state can be determined by monitoring the oxidation and reduction of [1-13C]ascorbate and [1-13C]dehydroascorbate respectively. Tumour glycolysis can be monitored by measuring the conversion of hyperpolarized [U-2H, U-13C]glucose to lactate and there is evidence that we can also detect pentose phosphate pathway flux from 6-phosphogluconate labelling. In a genetically engineered mouse model of pancreatic cancer we have shown that hyperpolarized [1-13C]pyruvate can be used to follow progression of precursor lesions (4) and more recently in patient-derived orthotopically implanted xenograft models of glioma that flux of 13C label between lactate and pyruvate varies between tumours derived from different patients and that this reflects expression of c-Myc (5). Imaging with hyperpolarized [1-13C]pyruvate has translated to the clinic and this has included studies in Cambridge. The metabolism of these hyperpolarized 13C-labelled substrates, and also novel ones that we are developing, report on various aspects of tumour metabolism, which in turn reflects the mutational status of the tumours. In this project the student will explore the extent to which non-invasive metabolic imaging with hyperpolarized 13C-labelled metabolites can be used to interrogate the underlying mutations that are driving tumour cell proliferation in patient-derived xenograft models of breast, ovarian and brain (glioma) cancer and therefore whether these imaging techniques could be used clinically to inform prognosis and treatment selection.

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.

Preferred skills/knowledge Applicants should have excellent communication and team working skills with a degree in the physical or biomedical sciences. A Master’s degree is not essential but some laboratory experience would be beneficial.