Metformin increases 18F-FDG flux and inhibits fatty acid oxidation at clinical doses in breast cancer: results of a phase 0 clinical trial


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Simon Lord1,Dan Liu1,Wei-Chen Cheng1,Syed Haider1,Edoardo Gaude2,Eugene Teoh1,Neel Patel1,Tom Metcalf3,Daniel McGowan1,Ioannis Roxanis1,Zhang Qifeng4,Pankaj Roy5,Fergus Gleeson1,Alastair Thompson6,Michael Pollak7,Michael Wakelam4,Francesca Buffa1,Christian Frezza2,John Fenwick3,Adrian Harris1
1University of Oxford,2University of Cambridge,3University of Liverpool,4Babraham Institute,5Oxford University Hospitals NHS Foundation Trust,6MD Andersen Cancer Centre,7McGill University

Abstract

Background

Over 100 clinical trials are underway worldwide to investigate the anticancer effects of the diabetes drug, metformin. However, it is still not determined as to whether metformin has significant direct effects on cancer cells or solely indirect effects via modulation of host metabolism.

Method

We recruited 41 non-diabetic patients with primary breast cancer to a neoadjuvant window trial. Patients received an escalating dose of metformin to 1500mg for 2 weeks with pre- and post-metformin pharmacodynamic assessments including, dynamic 18F-FDG PET-CT scans, serum metabolic markers, and tumour biopsies for whole transcriptome RNASeq, tumour metabolomics and immunohistochemistry.

Results

Assessment of tumour FDG kinetics using a classic 2-tissue compartment model with three rate constants showed a 1.3 fold change (FC) post-metformin in the composite 18F-FDG flux constant, Kflux (p = 0.041, paired t-test). Mass spectrometry analysis revealed a decrease in intratumoral levels of propionylcarnitine (FC -0.50, p = 0.039) and acetylcarnitine (FC -0.40, p = 0.046) consistent with inhibition of fatty acid oxidation (wilcoxon rank test). This effect on fatty acid oxidation was validated in pre-clinical in vitro and in vivo breast cancer cell line models. RNASeq revealed upregulation of several pathways associated with mitochondrial and lipid metabolism. Immunohistochemical intratumoral nuclear expression of pAMPK increased 1.5 fold (p = 0.037, paired t-test). Serum glucose, c-peptide, insulin and IGF-1 levels significantly decreased but did not correlate with change in Kflux or short chain acyl-carnitine levels. Peak serum metformin levels correlated with intratumoral metformin levels (p = 0.012, Spearman’s rank test).

Conclusion

Our data shows that metformin treatment increases 18F-FDG flux, inhibits fatty acid oxidation and leads to altered gene expression in the mitochondrial (nuclear encoded) transcriptome but that these effects do not correlate with changes in host metabolism. This data provides strong evidence that metformin has a direct effect on breast cancer metabolism at clinical doses.

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