Imaging tumour glycolysis and pentose phosphate pathway activity with hyperpolarized 13C-labelled glucose
In order to generate the energy required to support rapid cell division, cancer cells display altered metabolic pathways. The best-characterised change is the switch in glucose metabolism and ATP production from oxidative phosphorylation to glycolysis, known as the Warburg Effect, resulting in increases in lactate production. By measuring changes in cell metabolites, we can potentially detect cell death. Imaging-based methods to explore changes in metabolism would offer a non-invasive approach to assess early treatment response.
Cambridge has been developing methods for detecting changes in tumour cell metabolism using hyperpolarised 13C-labelled cell metabolites. Nuclear spin hyperpolarisation can increase sensitivity in the MR experiment by greater than 10,000-fold, which has allowed us to image the location of labelled cell substrates and, more importantly, their metabolic conversion into other metabolites in vivo. We showed that exchange of hyperpolarised 13C label between lactate and pyruvate can be imaged in animal models of lymphoma and glioma and that this flux is decreased post-treatment. We showed that hyperpolarised [1,4-13C]fumarate can be used to detect tumour cell necrosis post treatment in lymphomas and that both the polarised pyruvate and fumarate experiments can detect early evidence of treatment response in a breast tumour model and also early responses to anti-vascular and anti-angiogenic drugs. Clinical trials with polarised pyruvate and fumarate to detect treatment response in lymphoma, glioma and breast cancer patients are due to begin in Cambridge in 2015.
Detection of treatment response with pyruvate is analogous to FDG-PET measurements of treatment response and indeed we have compared them directly. A limitation of both the FDG-PET and hyperpolarised pyruvate experiments is that they interrogate just small parts of tumour cell metabolism; glucose transport and hexokinase-dependent phosphorylation in the case of FDG-PET and pyruvate transport and LDH activity in the case of hyperpolarised pyruvate. We might anticipate that a metabolic imaging technique that samples more of the aberrant glucose metabolism of tumour cells would be more sensitive in detecting treatment response. We have recently made a breakthrough in this regard by showing that hyperpolarised [U-2H, U-13C]glucose can be used to detect treatment response in a murine lymphoma in vivo, response being detected through a decrease in lactate labelling. We have also shown that we can detect hyperpolarised 13C label flux into 6-phosphogluconate, which can be used to assess flux into the pentose phosphate pathway. Flux in this pathway is up-regulated in tumours in order to combat the high levels of oxidative stress that they experience and is correlated with resistance to chemotherapy.
We will compare hyperpolarised 13C-labelled glucose with other methods for detecting treatment response, including FDG-PET, hyperpolarised pyruvate and fumarate, diffusion-weighted MR imaging and a targeted imaging agent for detecting cell death, and therefore investigate its potential as a new tool for detecting tumour responses to treatment. We will also investigate the capability of hyperpolarised 13C-labelled glucose for providing real-time assessments of flux into the pentose phosphate pathway and thus the potential of tumours to resist oxidative stress.
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Professor Kevin BrindleChair in
Biomedical Magnetic Resonance at the University of Cambridge
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Dr Ferdia Gallagher
Cancer Research UK Clinician Scientist Fellow at the Cancer Research UK Cambridge Institute and Honorary Consultant at Cambridge University Hospitals NHS Foundation Trust.
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