Simultaneous targeting of glycolysis and oxidative phosphorylation as a therapeutic strategy to treat diffuse large B-cell lymphoma.

Autor: Noble RA; Cancer Research Horizons Therapeutic Innovation, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK., Thomas H; Cancer Research Horizons Therapeutic Innovation, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK., Zhao Y; Cancer Research Horizons Therapeutic Innovation, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK., Herendi L; Department of Surgery & Cancer and Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK., Howarth R; Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK., Dragoni I; Centre for Drug Development, Cancer Research UK, London, UK., Keun HC; Department of Surgery & Cancer and Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK., Vellano CP; TRACTION Platform, Therapeutics Discovery Division, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA., Marszalek JR; TRACTION Platform, Therapeutics Discovery Division, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA., Wedge SR; Cancer Research Horizons Therapeutic Innovation, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK. steve.wedge@ncl.ac.uk.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2022 Sep; Vol. 127 (5), pp. 937-947. Date of Electronic Publication: 2022 May 26.
DOI: 10.1038/s41416-022-01848-w
Abstrakt: Background: We evaluated the therapeutic potential of combining the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 with the mitochondrial respiratory Complex I inhibitor IACS-010759, for the treatment of diffuse large B-cell lymphoma (DLBCL), a potential clinically actionable strategy to target tumour metabolism.
Methods: AZD3965 and IACS-010759 sensitivity were determined in DLBCL cell lines and tumour xenograft models. Lactate concentrations, oxygen consumption rate and metabolomics were examined as mechanistic endpoints. In vivo plasma concentrations of IACS-010759 in mice were determined by LC-MS to select a dose that reflected clinically attainable concentrations.
Results: In vitro, the combination of AZD3965 and IACS-010759 is synergistic and induces DLBCL cell death, whereas monotherapy treatments induce a cytostatic response. Significant anti-tumour activity was evident in Toledo and Farage models when the two inhibitors were administered concurrently despite limited or no effect on the growth of DLBCL xenografts as monotherapies.
Conclusions: This is the first study to examine a combination of two distinct approaches to targeting tumour metabolism in DLBCL xenografts. Whilst nanomolar concentrations of either AZD3965 or IACS-010759 monotherapy demonstrate anti-proliferative activity against DLBCL cell lines in vitro, appreciable clinical activity in DLBCL patients may only be realised through their combined use.
(© 2022. The Author(s).)
Databáze: MEDLINE
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