Purpose: By taking advantage of 18F-FDG PET imaging and tissue nuclear magnetic resonance (NMR) metabolomics, we examined the dynamic metabolic alterations induced by liver irradiation in a mouse model for hepatocellular carcinoma (HCC). Methods: After orthotopic implantation with the mouse liver cancer BNL cells in the right hepatic lobe, animals were divided into two experimental groups. The first received irradiation (RT) at 15 Gy, while the second (no-RT) did not. Intergroup comparisons over time were performed, in terms of 18F-FDG PET findings, NMR metabolomics results, and the expression of genes involved in inflammation and glucose metabolism. Results: As of day one post-irradiation, mice in the RT group showed an increased 18F-FDG uptake in the right liver parenchyma compared with the no-RT group. However, the difference reached statistical significance only on the third post-irradiation day. NMR metabolomics revealed that glucose concentrations peaked on day one post-irradiation both, in the right and left lobes—the latter reflecting a bystander effect. Increased pyruvate and glutamate levels were also evident in the right liver on the third post-irradiation day. The expression levels of the glucose-6-phosphatase (G6PC) and fructose-1, 6-bisphosphatase 1 (FBP1) genes were down-regulated on the first and third post-irradiation days, respectively. Therefore, liver irradiation was associated with a metabolic shift from an impaired gluconeogenesis to an enhanced glycolysis from the first to the third post-irradiation day. Conclusion: Radiation-induced metabolic alterations in the liver parenchyma occur as early as the first post-irradiation day and show dynamic changes over time.

We aim to establish a noninvasive diagnostic platform to capture early phenotypic transformation for metastasis using ¹⁸F-FDG PET and ¹H-NMR-based serum metabolomics. Mice with implantation of NCI-H460 cells grew only primary lung tumors in the localized group and had both primary and metastatic lung tumors in the metastatic group. The serum metabolites were analyzed using ¹H-NMR at the time of PET/CT scan. The glycolysis status and cell proliferation were validated by Western blotting and staining. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic accuracy of SUV_mean and serum metabolites in metastasis. In the metastatic mice, the SUV_mean of metastatic tumors was significantly higher than that of primary lung tumors in PET images, which was supported by elevated glycolytic protein expression of HK2 and PKM2. The serum pyruvate level in the metastatic group was significantly lower than that in the localized group, corresponding to increased pyruvate-catalyzed enzyme and proliferation rates in metastatic tumors. In diagnosing localized or metastatic tumors, the areas under the ROC curves of SUV_mean and pyruvate were 0.92 and 0.91, respectively, with p < 0.05. In conclusion, the combination of ¹⁸F-FDG PET and ¹H-NMR-based serum metabolomics demonstrated the feasibility of a glycolytic platform for diagnosing metastatic lung cancers.

Background: Given the heterogeneity and high mortality associated with metastatic soft tissue sarcoma, this study aims to evaluate the therapeutic efficacy of combining 177Lu-FAPI-46 with Pazopanib against this malignancy. Methods: Patient-derived xenograft (PDX)-bearing mice were randomly divided into three groups: the control group, the 177Lu-FAPI-46 monotherapy group, and the 177Lu-FAPI-46 combined with Pazopanib therapy group. Therapeutic efficacy was regularly monitored. Results: The microPET imaging showed a 0.84-fold decrease in the T/M ratio of 68Ga-FAPI-46 on day 7/8 post combination therapy, while the control group exhibited a 1.23-fold increase. Combination therapy significantly inhibited tumor proliferation, as evidenced by reduced Ki-67 and increased caspase 3 expressions. Notably, there was no significant body weight loss observed in any group. Conclusion: This study successfully demonstrated the reduction in FAP expression and suppression of tumor volume in sarcoma PDX following the combination therapy of 177Lu-FAPI-46 with Pazopanib.

We aim to characterize the metabolic changes associated with early response to radiation therapy in a prostate cancer mouse model by 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) and [¹¹C]acetate ([¹¹C]ACT) positron emission tomography, with nuclear magnetic resonance (NMR) metabolomics corroboration. [¹⁸F]FDG and [¹¹C]ACT PET were performed before and following irradiation (RT, 15Gy) for transgenic adenocarcinoma of mouse prostate xenografts. The underlying metabolomics alterations of tumor tissues were analyzed by using ex vivo NMR. The [¹⁸F]FDG total lesion glucose (TLG) of the tumor significant increased in the RT group at Days 1 and 3 post-irradiation, compared with the non-RT group (p < 0.05). The [¹¹C]ACT maximum standard uptake value (SUVmax) in RT (0.83 ± 0.02) and non-RT groups (0.85 ± 0.07) were not significantly different (p > 0.05). The ex vivo NMR analysis showed a 1.70-fold increase in glucose and a 1.2-fold increase in acetate in the RT group at Day 3 post-irradiation (p < 0.05). Concordantly, the expressions of cytoplasmic acetyl-CoA synthetase in the irradiated tumors was overexpressed at Day 3 post-irradiation (p < 0.05). Therefore, TLG of [¹⁸F]FDG in vivo PET images can map early treatment response following irradiation and be a promising prognostic indicator in a longitudinal preclinical study. The underlying metabolic alterations was not reflected by the [¹¹C]ACT PET.

Radiation therapy for liver and upper abdominal malignancies is associated with a high risk of radiation-induced liver disease (RILD), often involving metabolic disturbances. This study aimed to characterize metabolomic alterations in a murine RILD model using ¹H-nuclear magnetic resonance (NMR) spectroscopy. RILD was induced in mice via 15 Gy hepatic irradiation. Liver tissues were subjected to time-course metabolomic profiling using ¹H NMR. Validation was performed through liver enzyme assays, histological analysis, and qPCR. Taurine was selected for therapeutic evaluation based on metabolomic findings. Significant reductions in glutathione and pyruvate levels were observed in the acute stage, whereas increases in phenylalanine and tyrosine levels were observed in the chronic stage. These metabolite alterations were correlated with reactive oxygen species (ROS) production, glycolysis modulation, and fibrosis progression in RILD. Notably, taurine levels increased during the acute stage but decreased during the chronic stage. Furthermore, in mice at 12 weeks postirradiation, taurine supplementation maintained liver enzyme activity, cytokine profiles, and taurine metabolism at levels similar to those of the control group. In conclusion, this study revealed dynamic metabolic changes associated with physiological alterations in a murine RILD model and identified, through ¹H NMR metabolomics, taurine as a potential target for alleviating nonclassical RILD symptoms.