Imperial College London
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ProfessorHectorKeun

Faculty of Medicine, Department of Surgery & Cancer

Professor of Biochemistry
 
 
 
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Contact

 

+44 (0)20 7594 3161h.keun

 
 
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Location

 

officesInstitute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Noble:2022:10.1038/s41416-022-01848-w,
author = {Noble, RA and Thomas, H and Zhao, Y and Herendi, L and Howarth, R and Dragoni, I and Keun, HC and Vellano, CP and Marszalek, JR and Wedge, SR},
doi = {10.1038/s41416-022-01848-w},
journal = {British Journal of Cancer},
pages = {937--947},
title = {Simultaneous targeting of glycolysis and oxidative phosphorylation as a therapeutic strategy to treat diffuse large B-cell lymphoma},
url = {http://dx.doi.org/10.1038/s41416-022-01848-w},
volume = {127},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - BackgroundWe 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.MethodsAZD3965 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.ResultsIn 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.ConclusionsThis 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.
AU  - Noble,RA
AU  - Thomas,H
AU  - Zhao,Y
AU  - Herendi,L
AU  - Howarth,R
AU  - Dragoni,I
AU  - Keun,HC
AU  - Vellano,CP
AU  - Marszalek,JR
AU  - Wedge,SR
DO  - 10.1038/s41416-022-01848-w
EP  - 947
PY  - 2022///
SN  - 0007-0920
SP  - 937
TI  - Simultaneous targeting of glycolysis and oxidative phosphorylation as a therapeutic strategy to treat diffuse large B-cell lymphoma
T2  - British Journal of Cancer
UR  - http://dx.doi.org/10.1038/s41416-022-01848-w
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000805462400003&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://www.nature.com/articles/s41416-022-01848-w
UR  - http://hdl.handle.net/10044/1/97953
VL  - 127
ER  -
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