Current Opportunities and Challenges of Magnetic Resonance Spectroscopy, Positron Emission Tomography, and Mass Spectrometry Imaging for Mapping Cancer Metabolism In Vivo

Cancer is known to have unique metabolic features such as Warburg effect. Current cancer therapy has moved forward from cytotoxic treatment to personalized, targeted therapies, with some that could lead to specific metabolic changes, potentially monitored by imaging methods. In this paper we addressed the important aspects to study cancer metabolism by using image techniques, focusing on opportunities and challenges of magnetic resonance spectroscopy (MRS), dynamic nuclear polarization (DNP)-MRS, positron emission tomography (PET), and mass spectrometry imaging (MSI) for mapping cancer metabolism. Finally, we highlighted the future possibilities of an integrated in vivo PET/MR imaging systems, together with an in situ MSI tissue analytical platform, may become the ultimate technologies for unraveling and understanding the molecular complexities in some aspects of cancer metabolism. Such comprehensive imaging investigations might provide information on pharmacometabolomics, biomarker discovery, and disease diagnosis, prognosis, and treatment response monitoring for clinical medicine

Cancer Metabolism and Tumor Heterogeneity: Imaging Perspectives Using MR Imaging and Spectroscopy

Cancer cells reprogram their metabolism to maintain viability via genetic mutations and epigenetic alterations, expressing overall dynamic heterogeneity. The complex relaxation mechanisms of nuclear spins provide unique and convertible tissue contrasts, making magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) pertinent imaging tools in both clinics and research. In this review, we summarized MR methods that visualize tumor characteristics and its metabolic phenotypes on an anatomical, microvascular, microstructural, microenvironmental, and metabolomics scale. The review will progress from the utilities of basic spin-relaxation contrasts in cancer imaging to more advanced imaging methods that measure tumor-distinctive parameters such as perfusion, water diffusion, magnetic susceptibility, oxygenation, acidosis, redox state, and cell death. Analytical methods to assess tumor heterogeneity are also reviewed in brief. Although the clinical utility of tumor heterogeneity from imaging is debatable, the quantification of tumor heterogeneity using functional and metabolic MR images with development of robust analytical methods and improved MR methods may offer more critical roles of tumor heterogeneity data in clinics. MRI/MRS can also provide insightful information on pharmacometabolomics, biomarker discovery, disease diagnosis and prognosis, and treatment response. With these future directions in mind, we anticipate the widespread utilization of these MR-based techniques in studying in vivo cancer biology to better address significant clinical needs

Synergistic antiproliferative effects of an mTOR inhibitor (rad001) plus gemcitabine on cholangiocarcinoma by decreasing choline kinase activity

Although gemcitabine plus cisplatin is the gold standard chemotherapy regimen for advanced cholangiocarcinoma, the response rate has been disappointing. This study aims to investigate a novel therapeutic regimen [gemcitabine plus everolimus (rad001), an mTOR inhibitor] for cholangiocarcinoma. Gemcitabine, oxaliplatin, cetuximab and rad001 in various combinations were first evaluated in vitro using six cholangiocarcinoma cell lines. In vivo therapeutic efficacies of gemcitabine and rad001 alone and their combination were further evaluated using a xenograft mouse model and a chemically induced orthotopic cholangiocarcinoma rat model. In the in vitro study, gemcitabine plus rad001 exerted a synergistic therapeutic effect on the cholangiocarcinoma cells, irrespective of the KRAS mutation status. In the xenograft study, gemcitabine plus rad001 showed the best therapeutic effect on tumor volume change, and was associated with increased caspase-3 expression, decreased eIF4E expression, as well as overexpression of both death receptor- and mitochondrial apoptotic pathway-related genes. In a chemically induced cholangiocarcinoma-afflicted rat model, the gemcitabine plus rad001 treatment suppressed tumor glycolysis as measured by 18F-fludeoxyglucose micro-positron emission tomography. Also, increased intratumoral free choline, decreased glycerophosphocholine and nearly undetectable phosphocholine levels were demonstrated by proton nuclear magnetic resonance, supported by results of decreased choline kinase expression in western blotting. We concluded that gemcitabine plus rad001 has a synergistic antiproliferative effect on cholangiocarcinoma, irrespective of the KRAS mutation status. The antitumor effect is associated with activation of both death receptor and mitochondrial pathways, as well as the downregulation of choline kinase activity, resulting in a characteristic change in choline metabolism

Response to Brigatinib Targeted Therapy in Non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Exon 19 Deletion, T790M, and cis-C797S Triple Mutations: A Case Report

Epidermal growth factor receptor (EGFR) triple mutations with exon 19 deletion (del19), T790M, and cis-C797S (del19/T790M/cis-C797S mutations) frequently occur in patients with non-small cell lung cancer (NSCLC), while progression to frontline EGFR-tyrosine kinase inhibitors (TKIs) and osimertinib was resistant to all clinically available EGFR-TKIs. Brigatinib monotherapy may be a potential treatment for NSCLC harboring del19/T790M/cis-C797S mutations based on preclinical studies; however, no clinical report has evaluated its efficacy on EGFR del19/T790M/cis-C797S mutations. Herein, we present a case of a female patient with EGFR del19-mutated NSCLC treated with afatinib followed by osimertinib due to acquired T790M mutation. The EGFR del19/T790M/cis-C797S mutations were detected following osimertinib treatment. Complete response of skull metastasis was confirmed after brigatinib treatment (90 mg daily). Unfortunately, she experienced intolerable adverse events; therefore, brigatinib was discontinued after three-month usage. This report provides the first reported evidence for the use of brigatinib monotherapy in patients with NSCLC harboring EGFR del19/T790M/cis-C797S mutations after progression to previous EGFR-TKIs

Metabolomic Signature of Diabetic Kidney Disease in Cerebrospinal Fluid and Plasma of Patients with Type 2 Diabetes Using Liquid Chromatography-Mass Spectrometry

Diabetic kidney disease (DKD) is the major cause of end stage renal disease in patients with type 2 diabetes mellitus (T2DM). The subtle metabolic changes in plasma and cerebrospinal fluid (CSF) might precede the development of DKD by years. In this longitudinal study, CSF and plasma samples were collected from 28 patients with T2DM and 25 controls, during spinal anesthesia for elective surgery in 2017. These samples were analyzed using liquid chromatography-mass spectrometry (LC-MS) in 2017, and the results were correlated with current DKD in 2017, and the development of new-onset DKD, in 2021. Comparing patients with T2DM having new-onset DKD with those without DKD, revealed significantly increased CSF tryptophan and plasma uric acid levels, whereas phosphatidylcholine 36:4 was lower. The altered metabolites in the current DKD cases were uric acid and paraxanthine in the CSF and uric acid, L-acetylcarnitine, bilirubin, and phosphatidylethanolamine 38:4 in the plasma. These metabolic alterations suggest the defective mitochondrial fatty acid oxidation and purine and phospholipid metabolism in patients with DKD. A correlation analysis found CSF uric acid had an independent positive association with the urine albumin-to-creatinine ratio. In conclusion, these identified CSF and plasma biomarkers of DKD in diabetic patients, might be valuable for monitoring the DKD progression

Exploring the aging process of cognitively healthy adults by analyzing cerebrospinal fluid metabolomics using liquid chromatography-tandem mass spectrometry

Abstract Background During biological aging, significant metabolic dysregulation in the central nervous system may lead to cognitive decline and neurodegeneration. However, the metabolomics of the aging process in cerebrospinal fluid (CSF) has not been thoroughly explored. Methods In this cohort study of CSF metabolomics using liquid chromatography-mass spectrometry (LC–MS), fasting CSF samples collected from 92 cognitively unimpaired adults aged 20–87 years without obesity or diabetes were analyzed. Results We identified 37 metabolites in these CSF samples with significant positive correlations with aging, including cysteine, pantothenic acid, 5-hydroxyindoleacetic acid (5-HIAA), aspartic acid, and glutamate; and two metabolites with negative correlations, asparagine and glycerophosphocholine. The combined alterations of asparagine, cysteine, glycerophosphocholine, pantothenic acid, sucrose, and 5-HIAA showed a superior correlation with aging (AUC = 0.982). These age-correlated changes in CSF metabolites might reflect blood–brain barrier breakdown, neuroinflammation, and mitochondrial dysfunction in the aging brain. We also found sex differences in CSF metabolites with higher levels of taurine and 5-HIAA in women using propensity-matched comparison. Conclusions Our LC–MS metabolomics of the aging process in a Taiwanese population revealed several significantly altered CSF metabolites during aging and between the sexes. These metabolic alterations in CSF might provide clues for healthy brain aging and deserve further exploration

1H Nuclear Magnetic Resonance (NMR)-Based Cerebrospinal Fluid and Plasma Metabolomic Analysis in Type 2 Diabetic Patients and Risk Prediction for Diabetic Microangiopathy

Insulin resistance and metabolic derangement are present in patients with type 2 diabetes mellitus (T2DM). However, the metabolomic signature of T2DM in cerebrospinal fluid (CSF) has not been investigated thus far. In this prospective metabolomic study, fasting CSF and plasma samples from 40 T2DM patients to 36 control subjects undergoing elective surgery with spinal anesthesia were analyzed by 1H nuclear magnetic resonance (NMR) spectroscopy. NMR spectra of CSF and plasma metabolites were analyzed and correlated with the presence of T2DM and diabetic microangiopathy (retinopathy, nephropathy, and neuropathy) using an area under the curve (AUC) estimation. CSF metabolomic profiles in T2DM patients vs. controls revealed significantly increased levels of alanine, leucine, valine, tyrosine, lactate, pyruvate, and decreased levels of histidine. In addition, a combination of alanine, histidine, leucine, pyruvate, tyrosine, and valine in CSF showed a superior correlation with the presence of T2DM (AUC:0.951), diabetic retinopathy (AUC:0.858), nephropathy (AUC:0.811), and neuropathy (AUC:0.691). Similar correlations also appeared in plasma profiling. These metabolic alterations in CSF suggest decreasing aerobic metabolism and increasing anaerobic glycolysis in cerebral circulation of patients with T2DM. In conclusion, our results provide clues for the metabolic derangements in diabetic central neuropathy among T2DM patients; however, their clinical significance requires further exploration

Developing a Method to Estimate the Downstream Metabolite Signals from Hyperpolarized [1-¹³C]Pyruvate

Hyperpolarized carbon-13 MRI has the advantage of allowing the study of glycolytic flow in vivo or in vitro dynamically in real-time. The apparent exchange rate constant of a metabolite dynamic signal reflects the metabolite changes of a disease. Downstream metabolites can have a low signal-to-noise ratio (SNR), causing apparent exchange rate constant inconsistencies. Thus, we developed a method that estimates a more accurate metabolite signal. This method utilizes a kinetic model and background noise to estimate metabolite signals. Simulations and in vitro studies with photon-irradiated and control groups were used to evaluate the procedure. Simulated and in vitro exchange rate constants estimated using our method were compared with the raw signal values. In vitro data were also compared to the Area-Under-Curve (AUC) of the cell medium in 13C Nuclear Magnetic Resonance (NMR). In the simulations and in vitro experiments, our technique minimized metabolite signal fluctuations and maintained reliable apparent exchange rate constants. In addition, the apparent exchange rate constants of the metabolites showed differences between the irradiation and control groups after using our method. Comparing the in vitro results obtained using our method and NMR, both solutions showed consistency when uncertainty was considered, demonstrating that our method can accurately measure metabolite signals and show how glycolytic flow changes. The method enhanced the signals of the metabolites and clarified the metabolic phenotyping of tumor cells, which could benefit personalized health care and patient stratification in the future