Epidemiological studies suggest that treatment with metformin in patients with type 2 diabetes mellitus reduces the incidence of cancer at a number of tumour sites. The mechanism of action of metformin on tumour cells, however, has remained unclear. In addition, much of the preclinical data are limited as studies in some models used doses of metformin many times higher than those used in the clinic. Now, in a clinically relevant study, Simon Lord and colleagues have shown that metformin activates multiple transcriptomic pathways associated with mitochondrial metabolism.

“Key questions remained unanswered regarding the effects of metformin in tumour cells at standard clinical doses,” explains Lord. “[Therefore,] we designed an in-depth study to try and answer some of the questions and explored potential biomarkers that could be used to stratify patients in current and future late phase trials.”

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In the present study, the authors expanded on their previous experience of running clinical studies by integrating novel imaging and transcriptomics, coupled with metabolomic profiling, to investigate the pharmacodynamic effects of metformin in cancer. Lord and colleagues report that metformin increased FDG (a marker of glucose uptake) flux into tumours and altered the concentration of a number of mitochondrial metabolites. Furthermore, an integrated analysis of their data sets demonstrated differential metabolic responses to therapy between patients.

“Drug studies that utilize novel imaging alongside tissue-based assays as a tool for understanding the bioactivity of an anticancer therapy is not routine during drug development,” concludes Lord. “Future studies of similar design, if carried out at an early stage of drug development, could optimize late phase trial design and address questions surrounding selection of patients and potential drug combinations.”