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]fumarate9,10.
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).