Abstract
SummaryLate-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time points to profile the bioactivity of metformin in primary breast cancer. We show metformin reduces the levels of mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumors. Two tumor groups are identified with distinct metabolic responses, an OXPHOS transcriptional response (OTR) group for which there is an increase in OXPHOS gene transcription and an FDG response group with increased 18-FDG uptake. Increase in proliferation, as measured by a validated proliferation signature, suggested that patients in the OTR group were resistant to metformin treatment. We conclude that mitochondrial response to metformin in primary breast cancer may define anti-tumor effect.
Highlights
Metformin can reduce proliferation of cancer cell lines in vitro and in vivo, and this effect has been ascribed to inhibition of mitochondrial complex 1 (Wheaton et al, 2014)
We present the results of a clinical study that integrates tumor metabolomic profiling with dynamic imaging, transcriptomics, and systemic metabolic markers to further dissect the effects of metformin on systemic and breast tumor metabolism
Using an irreversible two-tissue compartment model describing rates of FDG transport and phosphorylation (STAR Methods), we observed an increase in FDG flux (KFDG) into the primary breast cancer following metformin (Figure 1B) but no change in the static uptake measures SULmax and SULmean for tumor (Figures S1A and S1B; Table S3)
Summary
Metformin can reduce proliferation of cancer cell lines in vitro and in vivo, and this effect has been ascribed to inhibition of mitochondrial complex 1 (Wheaton et al, 2014). Controversy remains as to whether metformin’s effects on tumor metabolism at clinical doses are determined by its direct effects on mitochondria or through its action on systemic metabolism via AMPK-dependent inhibition of hepatic gluconeogenesis and subsequent reduced circulating glucose and insulin levels. The response to metformin seen in the human metabolite profiles could be recapitulated in a mouse model and in vitro when nutrient concentrations were limited (Liu et al, 2016). To date, this is the most convincing clinical evidence that metformin has significant and measurable mitochondrial effects at standard therapeutic doses. We present the results of a clinical study that integrates tumor metabolomic profiling with dynamic imaging, transcriptomics, and systemic metabolic markers to further dissect the effects of metformin on systemic and breast tumor metabolism
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