Molecular imaging is likely to play an increasingly important role in predicting and detecting tumor responses to treatment and thus in guiding treatment in individual patients. Nuclear spin hyperpolarization increases sensitivity in the ¹³C magnetic resonance experiment by >10,000x.  This unprecedented increase in sensitivity has allowed ¹³C magnetic resonance imaging of injected hyperpolarized ¹³C labelled cell substrates in vivo and, more importantly, the kinetics of their metabolic conversion into other cell metabolites.  We have used this imaging technique, which has translated to the clinic, to detect tumor treatment response, to monitor disease progression and to investigate the tumor microenvironment (reviewed in ¹).

Exchange of hyperpolarized ¹³C label between lactate and pyruvate frequently decreases following successful treatment and can provide an early indication of treatment response.  Since PET measurements of tumour uptake of the glucose analog 2-([¹⁸F]fluoro)-2-deoxy-D-glucose uptake (FDG-PET) are already used in the clinic for treatment response monitoring we have investigated what advantages the hyperpolarized ¹³C experiment might have.  We showed in a human colorectal xenograft model², and in patient-derived xenograft models of breast cancer³ that successful treatment resulted in an early decrease in lactate labelling, whereas there was no change in FDG uptake.  We have also used hyperpolarized [1-¹³C]pyruvate to investigate glycolytic metabolism in patient derived xenograft (PDX) models of glioblastoma, which showed significant metabolic heterogeneity between tumours derived from different patients⁴.  Some clinical results in breast cancer⁵ and glioma patients⁶ will be presented.  Although we have used hyperpolarized [U-²H, U-¹³C]glucose to image glycolysis in murine tumour models⁷ the method does not provide a quantitative measurement of glycolytic flux and moreover would be difficult to implement clinically because of the short ¹³C hyperpolarization lifetime in vivo (~10 s).  More recently we have shown that we can use dynamic ²H MRI to provide quantitative measurements of tumour glycolytic flux following injection of d-[6,6’-²H₂]glucose⁸.  These showed that glycolytic flux was heterogeneous in a murine tumour model and that this showed a rapid decrease following successful tumour treatment.  We had shown previously that we could detect tumour cell death in vivo by imaging the conversion of hyperpolarized [1,4-¹³C₂]fumarate to [1,4-¹³C₂]malate.  We have shown more recently that this can also be accomplished by ²H imaging with [2,3-²H₂]fumarate^9,10.

References

1          Brindle, K. M. Imaging Metabolism with Hyperpolarized ¹³C-Labeled Cell Substrates. J. Amer. Chem. Soc. 137, 6418-6427 (2015).

2          Hesketh, R. L. et al. Magnetic Resonance Imaging Is More Sensitive Than PET for Detecting Treatment-Induced Cell Death-Dependent Changes in Glycolysis. Cancer Research 79, 3557-3569(2019).

3          Ros, S. et al. Metabolic Imaging Detects Resistance to PI3Kα Inhibition Mediated by Persistent FOXM1 Expression in ER+ Breast Cancer. Cancer Cell 38, 1-18(2020).

4          Mair, R. et al. Metabolic Imaging Detects Low Levels of Glycolytic Activity That Vary with Levels of c-Myc Expression in Patient-Derived Xenograft Models of Glioblastoma. Cancer Res 78, 5408-5418, doi:10.1158/0008-5472.Can-18-0759 (2018).

5          Gallagher, F. A. et al. Imaging breast cancer using hyperpolarized carbon-13 MRI. Proceedings of the National Academy of Sciences 117, 2092-2098, doi:10.1073/pnas.1913841117 (2020).

6          Zaccagna, F. et al. Imaging Glioblastoma Metabolism by Using Hyperpolarized [1-13C]Pyruvate Demonstrates Heterogeneity in Lactate Labeling: A Proof of Principle Study. Radiology: Imaging Cancer 4, e210076(2022).

7          Rodrigues, T. B. et al. Magnetic resonance imaging of tumor glycolysis using hyperpolarized ¹³C-labeled glucose. Nat Med 20, 93-97(2014).

8          Kreis, F. et al. Measuring Tumor Glycolytic Flux in Vivo by Using Fast Deuterium MRI. Radiology 294, 289-296(2020).

9          Hesse, F. et al. Monitoring tumor cell death in murine tumor models using deuterium magnetic resonance spectroscopy and spectroscopic imaging. Proceedings of the National Academy of Sciences 118, e2014631118(2021).

10        Hesse, F. et al. Imaging glioblastoma response to radiotherapy using ²H magnetic resonance spectroscopy measurements of fumarate metabolism. Cancer Res In press (2022).

Kevin M. Brindle, D. Phil., is Professor of Biomedical Magnetic Resonance at the University of Cambridge and a Senior Group Leader in the Cancer Research UK Cambridge Institute.  He got his BA (Biochemistry,1978) and D. Phil (1982) in Oxford, before becoming a Royal Society University Research Fellow in 1986.  He moved to a lectureship in Manchester in 1990 and in 1993 to a lectureship in Cambridge, where he became Professor in 2005. He was elected a Fellow of the Academy of Medical Sciences in 2012, a Fellow of the European Academy of Cancer Sciences in 2014, a Fellow of the International Society of Magnetic Resonance in 2020 and a Fellow of the Royal Society in 2020. He was President of the European Society for Molecular Imaging in 2018 and was awarded the European Society of Molecular Imaging Award in 2013 and the Gold Medal of the World Molecular Imaging Society in 2014.

Cancer diagnosis and treatment is undergoing a radical shift away from a reactive approach to symptomatic disease to early diagnosis, including at the pre-cancerous stage. Oesophageal adenocarcinoma develops gradually from the pre-malignant condition Barrett’s oesophagus which presents an opportunity to radically improve outcomes from this highly aggressive cancer. Elucidation of the molecular landscape of Barrett’s samples over time and space, in patients with different outcomes, is shedding light on the pathogenesis of this disease. Molecular data obtained from our improved understanding of the disease can be applied to novel non-endoscopic detection devices to identify individuals at risk of cancer needing preventative treatment. Acceptability, affordability and access to technology are also critical to effective clinical translation and this seminar will map our multidisciplinary approach to developing new tools for early detection of oesophageal cancer without reliance on endoscopy.

Rebecca Fitzgerald MACantab. MD FMedSci EMBO is Professor of Cancer Prevention and Interim Director at the MRC Cancer Unit, University of Cambridge. She leads the Cambridge Early Detection Programme of the Cancer Research UK Cambridge Centre which is part of the International Alliance in Early Detection (ACED) and practices medicine as Hon. Consultant in Gastroenterology and Cancer Medicine at Addenbrooke's Hospital. The focus of her own research group is to investigate the steps in malignant transformation in the oesophagus and stomach and to use this information to improve clinical early detection strategies. Her work to develop and implement the Cytosponge and related biomarker assays for detection of Barrett's oesophagus and associated dysplasia has been awarded a number of prizes including the Westminster Medal, the BMJ Gastro team of the year, an NHS Innovation prize and the CRUK Jane Wardle Early Detection Prize. In 2013, she was elected as a Fellow of the Academy of Medical Sciences and in 2021 elected a Member of EMBO. Rebecca is committed to teaching and is a Fellow of Medical Sciences at Trinity College Cambridge.