MRI with hyperpolarised [1-¹³C]pyruvate detects advanced pancreatic preneoplasia prior to invasive disease in a mouse model

Abstract

ObjectivesPancreatic cancer (PCa) is treatable by surgery when detected at an early stage. Non-invasive imaging methods able to detect both established tumours and their precursor lesions are needed to select patients for surgery. We investigated here whether pancreatic preneoplasia could be detected prior to the development of invasive cancers in genetically engineered mouse models of PCa using metabolic imaging.DesignThe concentrations of alanine and lactate and the activities of lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) were measured in extracts prepared from the pancreas of animals at different stages of disease progression; from pancreatitis, through tissue with predominantly low-grade and then high-grade pancreatic intraepithelial neoplasia and then tumour. 13C magnetic resonance spectroscopic imaging (13C-MRSI) was used to measure non-invasively changes in 13C labelling of alanine and lactate with disease progression, following injection of hyperpolarised [1-13C]pyruvate.ResultsProgressive decreases in the alanine/lactate concentration ratio and ALT/LDH activity ratio with disease progression were accompanied by a corresponding decrease in the [1-13C]alanine/[1-13C]lactate signal ratio observed in 13C-MRSI images of the pancreas.ConclusionsMetabolic imaging with hyperpolarised [1-13C]pyruvate enables detection and monitoring of the progression of PCa precursor lesions. Translation of this MRI technique to the clinic has the potential to improve the management of patients at high risk of developing PCa.

A referenceless Nyquist ghost correction workflow for echo planar imaging of hyperpolarized [1‐13C]pyruvate and [1‐13C]lactate

“…For example, the imaging of hyperpolarized [1‐ 13 C]pyruvate and its downstream metabolic products has been used in cancer research to assess treatment response6, 7 and disease progression,8, 9 and in other tissues, such as heart10, 11 and kidney,12 to assess tissue function. The technique has now been translated to the clinic with studies in prostate cancer13 and in heart 14…”

Hyperpolarized 13C Magnetic Resonance Treatment Response Monitoring: A New Paradigm for Multiorgan Metabolic Assessment of Pharmacological Interventions?

“…This can be largely overcome by investigating the same patient several times, thus acting as his or her own control. This is particularly relevant in monitoring the effects of treatments and development of diseases over time (10).…”

“…A limiting factor is the decay of the signal, which limits the investigations to fast metabolic processes (currently less than 2 min). The use of hyperpolarized [1][2][3][4][5][6][7][8][9][10][11][12][13] C]pyruvate MRI provides an opportunity to combine the flexibility and safety of MR-based imaging with an exceptional signal-to-noise ratio. Exploration of injectable 13 C-labeled substances has only recently entered human trials (11).…”

Next-generation metabolic imaging in pancreatic cancer

“…5 Hyperpolarised [1-13 C]pyruvate MRSI has been applied in several preclinical animal tumour models to visualise substrate circulation and uptake via monocarboxylate transporters as well as label flux (ie, label exchange and net conversion) to In this issue of Gut, Serrao and colleagues performed metabolic imaging with hyperpolarised [1-13 C]pyruvate in mouse models of PDAC to test its feasibility for early disease detection and progression. 6 They used a genetically engineered mouse model system harbouring preneoplastic lesions and complex microenvironmental alterations that faithfully recapitulate the human disease. The authors report decreased alanine/lactate concentration and ALT/LDH activity ratios in tissue extracts and correspondingly decreased [1-13 C]alanine/[1-13 C]lactate signal ratios with disease progression following the injection of hyperpolarised [1-13 C]pyruvate in vivo.…”

“…This high-risk patient population would benefit from better surveillance screens to detect disease progression. In addition, hyperpolarised [1-13 C]pyruvate MRSI may enable the differentiation of mass forming pancreatitis and pancreatic cancer, as indicated by the lack of change in alanine/lactate concentration ratio observed in an experimental pancreatitis model compared with normal pancreas in the study by Serrao et al 6 Furthermore, hyperpolarised [1-13 C]pyruvate MRSI could enable early detection of metabolic tumour response to approaches that interfere with increased glucose metabolism, for example, LDH-A inhibitors. 9 In summary, this exciting study presents MRSI with hyperpolarised [1-13 C]pyruvate as a novel and promising noninvasive, radiation-free method for early detection of disease progression in developing pancreatic cancer, for example, in high-risk patients.…”