Imaging magnetised molecules could predict drug resistance

New research from the Brindle Group, working in collaboration with the Caldas Group, suggests that a scanning technique, called carbon-13 hyperpolarised imaging, could be used to predict treatment response in breast cancer patients. 

In many estrogen receptor (ER)-positive breast cancer cases, PI3Ka is permanently switched on, which means that the cancer cells grow uncontrollably. Drugs that inhibit PI3Ka are currently being tested in breast cancer patients, however, the patients’ tumours can have an innate resistance to these drugs, or can acquire resistance over time.

It is important to find reliable biomarkers to predict a patient’s response, as this will enable doctors to make better decisions about which patients could benefit from PI3Ka inhibitors.

The new study, published in Cancer Cell, found that persistent expression of the protein FOXM1 following treatment with PI3Ka inhibitors could be used as a biomarker for drug resistance in patients with ER⁺ breast cancer.

Our cells convert pyruvate into lactate as part of the metabolic processes that produce energy and the building blocks for making new cells. Tumours have a different metabolism to healthy cells, and often produce more lactate. This metabolic pathway is affected by the amount of FOXM1 present in the cell.

PI3Ka inhibitors, if working as expected, were shown to decrease the amount of FOXM1 protein in ER⁺ breast tumour models. However, if a tumour became resistant to PI3Ka inhibitors, FOXM1 expression persisted.

To check the expression of FOXM1 directly in a patient’s tumour would usually involve an invasive tissue biopsy. However, FOXM1 controls the expression of a metabolic enzyme that converts pyruvate into lactate. By using ‘hyperpolarised’, or magnetised, carbon-13-labelled pyruvate the team can detect if a tumour is sensitive or resistant to PI3Ka inhibitors, by measuring non-invasively and in real time how fast pyruvate is converted into lactate using an MRI scan.

In the future, a rapid assessment of treatment response in breast cancer patients using this imaging method could help identify patients that would benefit from drugs that inhibit PI3Kα. This imaging technique could also help in designing drug combinations that combat the emergence of resistance.

Dr Susana Ros, first author from the Cancer Research UK Cambridge Institute, said “We have found a biomarker of response and resistance to PI3Kα inhibitors in estrogen receptor positive breast cancer. Excitingly, we can detect expression of this biomarker using a new imaging technique which we hope could soon help to improve treatment in the clinic”.

“I am looking forward to testing this technique in patients, which could show whether a treatment is working or not within a few days. This information could help put an end to giving treatments that are not working and the side effects that accompany them. Currently, patients can wait a long time to find out if a treatment is working. This technique could shorten this time, and help to tailor treatment for individual patients.”

This research was made possible with the support of the Flow Cytometry, Genome Editing, Genomics, Histopathology, Microscopy, Research Instrumentation and Cell Services and Biological Resources Unit Core Facilities at the Institute.