Tracing nutrient flux following monocarboxylate transporter-1 inhibition with AZD3965

Braga, M. et al. (2020) Tracing nutrient flux following monocarboxylate transporter-1 inhibition with AZD3965. Cancers, 12(6), 1703. (doi: 10.3390/cancers12061703) (PMID:32604836) (PMCID:PMC7352845)

Abstract

The monocarboxylate transporter 1 (MCT1) is a key element in tumor cell metabolism and inhibition of MCT1 with AZD3965 is undergoing clinical trials. We aimed to investigate nutrient fluxes associated with MCT1 inhibition by AZD3965 to identify possible biomarkers of drug action. We synthesized an 18F-labeled lactate analogue, [18F]-S-fluorolactate ([18F]-S-FL), that was used alongside [18F]fluorodeoxyglucose ([18F]FDG), and 13C-labeled glucose and lactate, to investigate the modulation of metabolism with AZD3965 in diffuse large B-cell lymphoma models in NOD/SCID mice. Comparative analysis of glucose and lactate-based probes showed a preference for glycolytic metabolism in vitro, whereas in vivo, both glucose and lactate were used as metabolic fuel. While intratumoral L-[1-13C]lactate and [18F]-S-FL were unchanged or lower at early (5 or 30 min) timepoints, these variables were higher compared to vehicle controls at 4 h following treatment with AZD3965, which indicates that inhibition of MCT1-mediated lactate import is reversed over time. Nonetheless, AZD3965 treatment impaired DLBCL tumor growth in mice. This was hypothesized to be a consequence of metabolic strain, as AZD3965 treatment showed a reduction in glycolytic intermediates and inhibition of the TCA cycle likely due to downregulated PDH activity. Glucose ([18F]FDG and D-[13C6]glucose) and lactate-based probes ([18F]-S-FL and L-[1-13C]lactate) can be successfully used as biomarkers for AZD3965 treatment.

• Item Type: Articles
• Additional Information: This research was funded by Cancer Research UK, grants number C2536/A16584 and number C2563/A10337.
• Keywords: Monocarboxylate transporter 1, cancer metabolism, lactate, glycolysis, AZD3965, diffuse large B-cell lymphoma, metabolic flux, positron emission tomography (PET).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Gottlieb, Professor Eyal and Mackay, Dr Gillian and Schug, Dr Zachary

Creator Roles

Schug, Z. T.: Methodology, Formal analysis, Investigation
Mackay, G.: Methodology, Formal analysis, Investigation
Gottlieb, E.: Resources, Supervision

• Authors: Braga, M., Kaliszczak, M., Carroll, L., Schug, Z. T., Heinzmann, K., Baxan, N., Benito, A., Valbuena, G. N., Stribbling, S., Beckley, A., Mackay, G., Mauri, F., Latigo, J., Barnes, C., Keun, H., Gottlieb, E., and Aboagye, E. O.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancers
• Publisher: MDPI
• ISSN: 2072-6694
• ISSN (Online): 2072-6694
• Published Online: 26 June 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Cancers 12(6): 1703
• Publisher Policy: Reproduced under a Creative Commons License