Metabolic profiles of breast cancer linked to response to metformin treatment

 

(B)(extract): Static PET-CT images in coronal plane pre- and post-metformin are from an individual with an

increase in KFDG-2cpt following metformin;note increased uptake in axillary lymph nodes (circled).

 

 

An international collaborative team of medical oncologists, radiologists, cell biologists and bioinformaticians led from Oxford by Simon Lord and Adrian Harris, have identified different metabolic response to metformin in breast tumours that link to change in a transcriptomic proliferation signature.

Published last week in Cell Metabolism, the team integrated tumour metabolomic and transcriptomic signatures with dynamic FDG PET imaging to profile the bioactivity of metformin in primary breast cancer.

Simon Lord stated: “This study shows how the integrated study of dynamic response to a short window of treatment can inform our understanding of drug bioactivity including mechanism of action and resistance. Further work will look to identify how mutations in mitochondria may define the metabolic response of tumours.”

The group demonstrated that metformin reduces the levels of several mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumours.

The paper “Integrated pharmacodynamic analysis identifies two metabolic adaption pathways to metformin in breast cancer” defines two distinct metabolic signatures after metformin treatment, linked to mitochondrial metabolism. These differential metabolic signatures apparent in tumour biopsy samples, did not link to changes in systemic metabolic blood markers including insulin and glucose, suggesting metformin has a predominant direct effect on tumour cells. Analysis of the dynamic FDG-PET-CT data showed that this novel imaging technique may have potential to identify early response to treatment that is not apparent using standard static clinical FDG-PET-CT.

 

 

Key point summary of the study:

  • There is great interest in repurposing metformin, a diabetes drug, as a cancer treatment
  • Two distinct metabolic responses to metformin seen in primary breast cancer
  • Increased 18-FDG flux, a surrogate marker of glucose uptake, observed in primary breast tumours following metformin treatment
  • Multiple pathways associated with mitochondrial metabolism activated at the transcriptomic level
  • Further evidence that metformin’s predominant effects in breast cancer are driven by direct interaction with tumour mitochondria rather than its effects on ‘host’ glucose/insulin metabolism

 

The study has been funded by Cancer Research UK, the Engineering and Physical Sciences Research Council, the Medical Research Council, and the Breast Cancer Research Foundation.

 

The published paper can be found at:

https://www.cell.com/cell-metabolism/home

 

Content adapted from the original paper by Simon Lord et al.