Magnetic Resonance Imaging Is More Sensitive Than PET for Detecting Treatment-Induced Cell Death–Dependent Changes in Glycolysis

Abstract

Metabolic imaging has been widely used to measure the early responses of tumors to treatment. Here, we assess the abilities of PET measurement of [ 18 F]FDG uptake and MRI measurement of hyperpolarized [1-13 C]pyruvate metabolism to detect early changes in glycolysis following treatmentinduced cell death in human colorectal (Colo205) and breast adenocarcinoma (MDA-MB-231) xenografts in mice. A TRAIL agonist that binds to human but not mouse cells induced tumor-selective cell death. Tumor glycolysis was assessed by injecting [1,6-13 C 2 ]glucose and measuring 13 C-labeled metabolites in tumor extracts. Injection of hyperpolarized [1-13 C]pyruvate induced rapid reduction in lactate labeling. This decrease, which correlated with an increase in histologic markers of cell death and preceded decrease in tumor volume, reflected reduced flux from glucose to lactate and decreased lactate concentration. However, [ 18 F]FDG uptake and phosphorylation were maintained following treatment, which has been attributed previously to increased [ 18 F]FDG uptake by infiltrating immune cells. Quantification of [ 18 F]FDG uptake in flow-sorted tumor and immune cells from disaggregated tumors identified CD11b þ /CD45 þ macrophages as the most [ 18 F]FDG-avid cell type present, yet they represented <5% of the cells present in the tumors and could not explain the failure of [ 18 F]FDG-PET to detect treatment response. MRI measurement of hyperpolarized [1-13 C]pyruvate metabolism is therefore a more sensitive marker of the early decreases in glycolytic flux that occur following cell death than PET measurements of [ 18 F]FDG uptake. Significance: These findings demonstrate superior sensitivity of MRI measurement of hyperpolarized [1-13 C]pyruvate metabolism versus PET measurement of 18 F-FDG uptake for detecting early changes in glycolysis following treatmentinduced tumor cell death.

Measuring Tumor Glycolytic Flux in Vivo by Using Fast Deuterium MRI

“…However, both FDG and hyperpolarized [1- 13 C]pyruvate interrogate only limited aspects of the tumor glycolytic phenotype, and neither technique measures flux through the entire glycolytic pathway from glucose to lactate. This can be important in detecting treatment response; for example, there can be a posttreatment reduction in tumor glycolytic flux in the absence of any significant decrease in FDG uptake (12).…”

Hyperpolarized 13C MRI of Tumor Metabolism Demonstrates Early Metabolic Response to Neoadjuvant Chemotherapy in Breast Cancer

“…The limitations of our study were that the results are from one patient, and the response was assessed after a full cycle of chemotherapy, when there was already a decrease in tumor volume. Further studies are needed to assess whether the metabolic changes observed in this study precede changes in tumor volume, as has been demonstrated preclinically (23).…”

“…The technique is free of ionizing radiation, does not require a long uptake time (as is the case with fluorine 18 [ 18 F] fluorodeoxyglucose [FDG]), and, because it depends on lactate pool size, it assesses more of the glycolytic pathway than 18 F FDG PET, which effectively assesses the first two steps of glycolysis. A preclinical study recently demonstrated the superiority of hyperpolarized 13 C MRI over 18 F FDG PET in early response assessment in a breast cancer model ( 23 ). Lactate measurements using 1 H MR spectroscopy remain challenging in patients with breast cancer owing to the high abundance of lipids in breast tumors and surrounding fat tissue ( 24 ).…”

Glycolytic metabolism of pathogenic T cells enables early detection of GvHD by13C-MRI

“…fatty acid oxidation, glutaminolysis and others 49,54,55 . Since a wide range of metabolites are amenable to 13 C-metabolic tracing in vivo 56 , further characterization of immune metabolism over the entire course of GvHD is prudent and may elucidate unique features of early, ongoing and well-established GvHD in vivo 53 .…”