The use of hyperpolarised 13C-MRI in clinical body imaging to probe cancer metabolism

Abstract

Metabolic reprogramming is one of the hallmarks of cancer and includes the Warburg effect, which is exhibited by many tumours. This can be exploited by positron emission tomography (PET) as part of routine clinical cancer imaging. However, an emerging and alternative method to detect altered metabolism is carbon-13 magnetic resonance imaging (MRI) following injection of hyperpolarised [1-¹³C]pyruvate. The technique increases the signal-to-noise ratio for the detection of hyperpolarised ¹³C-labelled metabolites by several orders of magnitude and facilitates the dynamic, noninvasive imaging of the exchange of ¹³C-pyruvate to ¹³C-lactate over time. The method has produced promising preclinical results in the area of oncology and is currently being explored in human imaging studies. The first translational studies have demonstrated the safety and feasibility of the technique in patients with prostate, renal, breast and pancreatic cancer, as well as revealing a successful response to treatment in breast and prostate cancer patients at an earlier stage than multiparametric MRI. This review will focus on the strengths of the technique and its applications in the area of oncological body MRI including noninvasive characterisation of disease aggressiveness, mapping of tumour heterogeneity, and early response assessment. A comparison of hyperpolarised ¹³C-MRI with state-of-the-art multiparametric MRI is likely to reveal the unique additional information and applications offered by the technique.

Fig. 1. Glucose metabolism in cancer and its relevance for metabolic imaging.

Cancer cells frequently demonstrate increased levels of glycolysis including conversion of glucose into pyruvate and subsequently into lactate (the Warburg effect). Consequently, increased import of glucose into tumour cells is maintained by increased expression of glucose transporters (GLUT). The intravenously injected positron emission tomography (PET) tracer [¹⁸F]2-fluoro-2-deoxy-d-glucose ([¹⁸F]FDG) is similarly taken up via the same transporter and also undergoes subsequent phosphorylation catalysed by hexokinase; this phosphorylation prevents its subsequent export from the cell. Hyperpolarised [1-¹³C]pyruvate can be used to image metabolic alterations further down the glycolytic pathway. Monocarboxylate transporters (MCTs) mediate its uptake into cancer cells, where it undergoes reduction to [1-¹³C]lactate catalysed by lactate dehydrogenase (LDH), transamination to [1-¹³C]alanine by alanine-aminotransferase (ALT), or irreversible oxidative decarboxylation to acetyl Co-A, a reaction catalysed by pyruvate dehydrogenase (PDH). During the latter oxidation, the hyperpolarised ¹³C-label is transferred from the carboxyl (C1) position of pyruvate to ¹³CO₂ and is detectable on spectroscopic imaging as bicarbonate (H¹³CO₃⁻). An alternative fate of [1-¹³C]pyruvate is carboxylation via pyruvate carboxylase (PC) to [1-¹³C]oxaloacetic acid, which can then be metabolised to [1-¹³C]malate. Any fumarate that is formed through the reverse fumarase reaction is symmetrical and therefore any subsequent forward exchange via fumarase results in the production of four-carbon intermediates with the ¹³C-labelling also present at C4 ([4-¹³C]malate and [4-¹³C]oxalacetic acid). The metabolites of this pathway have been detected using hyperpolarised ¹³C-MRI in preclinical liver studies;^, increased conversion of pyruvate into oxaloacetic acid has been demonstrated in lung and breast cancer using non-imaging studies, which raises important applications for detecting this reaction more generally within tumours. However, none of these four-carbon intermediates have been detected in cancer using clinical hyperpolarised ¹³C-MRI. The ¹³C-label in the C1 position is shown as yellow circles and in the C4 position as red circles. For clarity, enzymatic cofactors and some of the additional substrates and products have been omitted. Other metabolic alterations relevant for cancer imaging are accumulation of 2-hydroxyglutarate (2HG) due to mutated isocitrate dehydrogenase (IDH) in the tricarboxylic acid cycle and accumulation of succinate due to succinate dehydrogenase (SDH) deficiency.

Fig. 2. Schematic of the hyperpolarisation process.

A solution of ¹³C-labelled pyruvate is doped with a free radical (electrons show in blue) to facilitate hyperpolarisation, while placed in a magnetic field of around 3.35–5 T, cooled to ~1 K (–272 °C), and irradiated with microwaves. After rapid dissolution and successful quality checks (temperature, pH etc.), the solution can be injected intravenously.

Fig. 3. Hyperpolarised ¹³C-MRI in a patient with metastatic prostate cancer.

Hyperpolarised ¹³C-MRI in a patient with metastatic prostate cancer undergoing androgen deprivation therapy before and after 6 weeks of treatment initiation. Representative axial T2-weighted (T2W) anatomic image and corresponding apparent diffusion coefficient (ADC) image, T2W image with an overlaid pyruvate-to-lactate metabolic exchange rate (k_PL) image and corresponding hyperpolarised ¹³C spectral array are shown. The 52-year-old prostate cancer patient with extensive high-grade prostate cancer was imaged a before therapy and b 6 weeks after initiation of androgen ablation and chemotherapy. Before treatment, the region of prostate cancer can be clearly seen (red arrows) as a reduction in signal on the T2W and ADC images, and increased hyperpolarised lactate and associated k_PL on hyperpolarised ¹³C-MRI. After initiation of androgen deprivation therapy there was a significant reduction in hyperpolarised lactate and k_PL to normal levels, with the prostate volume and ADC showing only a modest response to treatment. Reprinted from European Urology, volume 72, Aggarwal, R., Vigneron, D. B. & Kurhanewicz, J., Hyperpolarized 1-[13C]-pyruvate magnetic resonance imaging detects an early metabolic response to androgen ablation therapy in prostate cancer, pages 1028–1029, Copyright (2017), with permission from Elsevier.

Fig. 4. Hyperpolarised ¹³C-MRI in a case of triple-negative breast cancer (TNBC)

a Coronal T1 3D spoiled gradient echo (SPGR) MRI image. b Coronally reformatted DCE image at peak enhancement after intravenous injection of a gadolinium-based contrast agent. c Summed hyperpolarised ¹³C-pyruvate and d summed hyperpolarised ¹³C-lactate images. The area of low ¹³C-pyruvate and ¹³C-lactate signals in the centre of the tumour are likely to correspond to an area with low enhancement on DCE. e LAC/PYR map showing intratumoural heterogeneity. The dominant intratumoural heterogeneity was concordant between the DCE-MRI and hyperpolarised ¹³C-MRI images and represents decreased delivery of both the gadolinium-based contrast agent and ¹³C-pyruvate to the centre of the tumour. f, g Dynamic hyperpolarised ¹³C-pyruvate and ¹³C-lactate images acquired over 15 time points after intravenous injection of hyperpolarised [1-¹³C]pyruvate (delay = 12 seconds; temporal resolution = 4 seconds). h Top: ¹³C metabolite spectrum from a coronal dynamic IDEAL spiral CSI slice covering the tumour summed over 15 time points; Bottom: The axial image from the equivalent DCE-MRI data was taken at the timepoint of maximum tumour enhancement. ppm parts per million, IC NST invasive cancer of no specific type. This Figure was reproduced from (10.1073/pnas.1913841117), licenced under CC-BY-NC-ND (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Fig. 5. Hyperpolarised ¹³C-MRI on a patient with pancreatic cancer.

Top row: anatomical axial slice showing the pancreatic tumour (white arrow) and the exocrine pancreas (purple arrow); the green region of interest outlines the whole pancreas. The ADC is greatly reduced in the tumour tissue. Bottom row: high [1‐¹³C]pyruvate, [1‐¹³C]lactate and [1‐¹³C]alanine signals were observed in the pancreatic tumour, with images acquired >30 sec after injection of hyperpolarised [1‐¹³C]pyruvate. The spectrum acquired in the area of the pancreatic cancer shows [1‐¹³C]pyruvate, [1‐¹³C]lactate and [1‐¹³C]alanine peaks. Reprinted from with permission from John Wiley & Sons.