C13 Pyruvate/Fumarate

Hyperpolarisation (a process developed by the Brindle group) increases the MRI signal 10,000x fold and enables imaging of metabolites without the use of radioactivity. Pyruvate measures metabolism in the cancer cells, the decrease in change from pyruvate to lactate is measured as cell death occurs. Pyruvate essentially measures metabolism and can detect responses to treatment very quickly, for example response to a PI3K inhibitor. This technique is currently being employed in breast cancer imaging and has generated both publications and media interest. It is also under investigation for both Ovarian and Renal cancer.

A similar method can be employed to monitor the reaction between fumarate and malate during cell death but in this case an increase in signal is measured which is more robust as a readout when compared to detecting a decrease as in the case of pyruvate/lactate. Again, the hyperpolarisation increases the signal on the MRI so that there is no need for a radioactive imaging agent.

Fumarate measures necrotic cells which increase shortly after treatment. As a positive imaging agent, fumarate is less likely to have a problem with false positive signals.  The challenge with fumarate is to identify the optimal time after treatment to image.  Fumarate works as a cell death detection agent because it enters viable cells only very slowly on the timescale of the hyperpolarization.  When cells die either the enzyme fumarase can leak out of the cells or fumarate can enter the cells more quickly, the effect of either is that fumarate gains more rapid access to the enzyme.  Fumarase catalyses conversion of fumarate to malate (which is what is detected) and only needs water for this hydration reaction (so the enzyme can be active outside the cell). Fumarate detects recent cell death (cells long dead will have lost their fumarase activity), this is both an advantage and a drawback.  The detection of recent cell death post treatment is useful since this will be the cell death produced by the treatment, however, timing for the detection of fumarate conversion to malate is crucial and it is not yet clear what is optimal. The early studies will help to establish this and the timing is likely to be different between tumours.

This research was featured on itv news and in an article on the CRUK CC website.

Further detail can be found in the publications below:

Ursprung, S., et al,  Hyperpolarized 13C-Pyruvate Metabolism as a Surrogate for Tumor Grade and Poor Outcome in Renal Cell Carcinoma—A Proof of Principle Study, Cancers, Jan 2022.

Woitek, R., et al, Hyperpolarized carbon-13 MRI for very early response assessment of neoadjuvant chemotherapy in breast cancer patients, Cancer Research, Sept 2021.

Woitek, R and Gallagher, F. A., The use of hyperpolarised 13C-MRI in clinical body imaging to probe cancer metabolism, British Journal of Cancer, 28 Jan 2021.

Gallagher F., Woitek R. et al., Imaging breast cancer using hyperpolarized carbon-13 MRI, PNAS, 2020.

Woitek R. et al., Hyperpolarized 13C MRI of Tumor Metabolism Demonstrates Early Metabolic Response to Neoadjuvant Chemotherapy in Breast Cancer, Radiology: Imaging Cancer, 2020