Abstract 1944: Detection of metabolic change in glioblastoma after radiotherapy using hyperpolarized 13C-MRI: Glycolytic metabolism in cancer stem cell-like cell-derived tumor model

Abstract

Abstract OBJECTIVES: Since the cancer stem-like cells (CSCs) play an important role in the resistance against radiation therapy due to its different metabolic profile, investigation of the specific metabolic characteristics of CSCs is valuable. Dynamic nuclear polarization (DNP) technique using 13C-labeled substrates enables magnetic resonance imaging (MRI) to monitor specific enzymatic reactions in tumors. In this study, DNP-MRI along with hyperpolarized [1-13C] pyruvate was conducted to evaluate the metabolic change in glycolytic profiles after irradiation between a glioblastoma cell line and a CSC-derived glioma using orthotopic xenograft mouse model. A microarray analysis was also performed to compare to the imaging study. METHODS: DNP-MRI A 3T MRI scanner along with a custom-made head coil was used. To obtain hyperpolarized [1-13C] pyruvate, 30 μL of [1-13C] pyruvic acid containing 15 mM of OX063 (trityl radical compound) and 2.5 mM of the gadolinium chelate were polarized at 3.35 T and 1.4 K in the Hypersense DNP polarizer. The hyperpolarized sample dissolved in a buffered medium was injected via the tail vein followed by an acquisition of 13C-two-dimensional MR-spectroscopy to measure the pyruvate-to-lactate ratios (Lac/Pyr) in the tumor region and the contralateral normal brain separately. Cell lines A human glioblastoma cell line, U251 and a glioma CSC line, NSC11 were cultured for stereotactic intracranial injection. Animal model Orthotopic brain tumor model was developed in athymic nude mice by intracranial implantation. When the tumor volume reached 50 +/- 10 mm3 on T2-weighted MRI, a sequence of DNP-MRI scans was performed 24 hours before and 6, 16 and 24 after 6-Gy whole-brain irradiation (N = 4 each with a non-irradiated control group). Independently, a microarray analysis using the tumor tissue samples excised 6 and 24 hours after irradiation was performed on Affymetrix Human Genome U133 Plus 2.0 array. RESULTS: DNP-MRI showed a decrease in Lac/Pyr 6 and 16 hours after irradiation compared to the control group in U251 whereas no significant change was observed in the NSC11 tumor. The microarray analysis showed a significant down-regulation of lactate dehydrogenase A (LDH-A) expression in U251 6 and 24 hours after irradiation, consistent with the finding of DNP-MRI. In the microarray analysis, SIRT2 and KLF4 expression also changed in the U251 tumor, suggested to regulate the LDH-A activity/expression. CONCLUSION: DNP-MRI demonstrated the difference in radiation response in glycolytic metabolism between the glioblastoma cell line and the CSC-derived glioma. This technique might be a feasible diagnostic method evaluating metabolic profiles of the brain tumors in the clinical settings of pretreatment and post-treatment. Citation Format: Tatsuya Kawai, Murali C. Krishna, Tamalee Kramp, Jeffery R. Brender, Philip Tofilon, Kevin A. Camphausen. Detection of metabolic change in glioblastoma after radiotherapy using hyperpolarized 13C-MRI: Glycolytic metabolism in cancer stem cell-like cell-derived tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1944.