Application of Hyperpolarized 13C-MRI to Cancer Treatment: Real-Time Monitoring of Pyruvate Metabolic Fluxes in Vivo and Targeting Intratumor Metabolic Plasticity with Small Molecules

Abstract

INTRODUCTION: It is well known that Pyruvate (Pyr) metabolism, which contains 2 major metabolic fluxes (glycolysis and oxidative phosphorylation: OXPHOS) increase in many neoplasms to meet the demand of higher energy consumption during rapid cell growing. To develop a therapeutic strategy using small molecules that can inhibit the fluxes, visualizing intratumoral metabolic fluxes should be useful. METHODS: For in vitro and in vivo experiments with a pancreatic cancer cell line “MiaPaca-2 (MP2),” a lactate dehydrogenase inhibitor “NCI-006” was used for glycolysis inhibition and mitochondrial complex1 (MC1) inhibitor “IACS-010759 (IACS)” for OXPHOS inhibition. Hyperpolarized 13C-Pyr magnetic resonance spectroscopic imaging (HP-MRSI) was performed before and after administration of each or both to monitor inhibitor impact on metabolic flux in MP2 xenografts. RESULTS: HP-MRSI revealed that glycolysis in MP2 tumor was suppressed by NCI-006 (83.3 ± 4.4% decrease) and accelerated by IACS (88.6 ± 25.1% increase), and that 13C-Bicarbonate signal arising from OXPHOS (through the mitochondrion) decreased by 80.1% after IACS administration. These imaging findings are fully consistent with the effect of those inhibitors in vitro on the energy profile of MP2 using extracellular flux analyzer, suggesting that glycolysis and OXPHOS are essential to functionally maintain metabolic plasticity in vivo. In addition, combined treatment (NCI-006 and IACS) significantly suppressed tumor growth, compared with each single administration, indicating combined treatment suppressed the metabolic plasticity between the fluxes. CONCLUSION: With no need for tissue sampling, HP-MRSI is considered a noninvasive and reliable method to monitor intratumoral metabolic plasticity. The current proof of concept can be of great value in developing new therapeutic strategies against cancer using metabolic inhibitors.