Tracing nutrient flux following monocarboxylate transporter-1 inhibition with AZD3965

Marta Braga, Maciej Kaliszczak, Laurence Carroll, Zachary T. Schug, Kathrin Heinzmann, Nicoleta Baxan, Adrian Benito, Gabriel N. Valbuena, Stephen Stribbling, Alice Beckley, Gillian Mackay, Francesco Mauri, John Latigo, Chris Barnes, Hector Keun, Eyal Gottlieb, Eric O. Aboagye

Research output: Contribution to journalArticlepeer-review

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 an18F-labeled lactate analogue, [18F]-S-fluorolactate ([18F]-S-FL), that was used alongside [18F]fluorodeoxyglucose ([18F]FDG), and13C-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.

Original languageEnglish (US)
Article number1703
Pages (from-to)1
Number of pages1
JournalCancers
Volume12
Issue number6
DOIs
StatePublished - Jun 2020
Externally publishedYes

Keywords

  • AZD3965
  • Cancer metabolism
  • Diffuse large B-cell lymphoma
  • Glycolysis
  • Lactate
  • Metabolic flux
  • Monocarboxylate transporter 1
  • Positron emission tomography (PET)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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