Dr. Jurre Kamphorst and Dr. Grace McGregor have recently completed a Rosetrees-funded project at the Beatson Institute, Glasgow. Their research involves investigating metabolic pathways in more detail, and how this can be exploited in cancer. In this project, they were specifically interested in the mevalonate pathway and drug repurposing of statins to target cancer cells.
Grace worked on this project as part of her PhD research. In the early stages of their project, Jurre and Grace identified that the coenzyme Q branch of the mevalonate pathway was highly active in pancreatic, breast and prostate cancer cells. They next used statins to successfully block coenzyme Q synthesis, which led to reduced cancer cell proliferation. This finding was particularly interesting as much of the literature has focussed on the use of statins to target cholesterol synthesis. However, using stable-isotope tracers and a novel high-resolution mass-spectrometry approach, Grace and Jurre explored the mevalonate pathway and found this was not the mechanism of action in cancer cells. Taking their observations further, they mapped the metabolic compensation that occurs as a result of decreased coenzyme Q synthesis. Their most striking observation was of reduced oxidative phosphorylation and significantly elevated reactive oxygen species production. Jurre and Grace then tested a combination therapy strategy in cancer cells to target these changes and metabolic vulnerabilities that occur in cancer cells, when treated with statins. They showed that statins synergised with the MEK-inhibitor (AZD6244), which lowers xCT cystine transporter levels, to produce a robust anti-tumour response.
From this, Grace conducted in vivo metabolism studies to explore the pathway in a pancreatic mouse tumour model. Excitingly, the in vitro results held up in vivo, and indeed a synergistic dual drug treatment significantly increased tumour cell death compared to the control and single arm treatments. Their findings have been published in Cancer Research.
This is what Grace had to say,
“I absolutely loved my PhD and I am incredibly grateful for the support I received from Rosetrees and Cancer Research UK. I had the unique opportunity to explore metabolism in vivo and learn the vastly complex technique of mass-spectrometry. I didn’t quite realise how rare such a skillset was until I attended the Keystone Tumor Metabolism Conference in March 2019. It was here that I was offered a post-doctoral position in the prestigious lab of Professor Christian Metallo. I have taken everything I learned as a PhD student, from lab techniques to refining my approach to pushing a project forward, and I am now heading up my very own high-resolution mass-spectrometer. I am exploring complex lipid molecules in the context of breast cancer and hoping to develop this to look at breast cancer metastasis. I was ecstatic that a part of my thesis was able to culminate in a publication. Science is about communication and now I’ve put in my first piece of the cancer research puzzle I feel like a real scientist. I thank Rosetrees and CRUK for supporting me through my PhD, and I hope to continue laying puzzle pieces during my postdoc.”
Written by: Dr. Rebecca Downing, Dr. Grace McGregor, and Dr. Jurre Kamphorst