Cancer cells produce energy predominately by a high rate of glycolysis. It has been suggested that this change in metabolism is a fundamental cause of cancer. Dr Patrick Pollard aims to elucidate the alternative metabolic strategies used by cancer cells to proliferate, even under conditions of stress.
This podcast presents the research done by Dr Pollard whilst working in the Nuffield Department of Medicine.
Dr Pollard’s work is focused on a form of kidney cancer for which no effective therapy exists once it metastasizes. By integrating analyses of these cancer cells and novel models he hopes to provide insights into altered cancer metabolism and a real, innovative route into the design of therapies for various cancers.
Ultimately, medical research must translate into improved treatments for patients. At the Nuffield Department of Medicine, our researchers collaborate to develop better health care, improved quality of life, and enhanced preventative measures for all patients. Our findings in the laboratory are translated into changes in clinical practice, from bench to bedside.
How do cancer cells produce their energy?
PP: All cells use glucose from the diet, and they convert this through a series of pathways to generate energy. Another requirement for cells to produce energy is oxygen. It has been known for quite some time that cancer cells require more glucose than normal cells and also more recently we found out they don’t require as much oxygen. Cancer cells also have the ability to use alternative pathways to generate the energy. This is the main focus of our group - to try and elucidate these alternative mechanisms and how they may give cancer cells a growth survival.
What happens when there are defects in the cells pathways?
PP: Cells can use many alternative pathways to generate energy. Two important pathways are glycolysis and the Krebs cycle. Both of these are a series of reactions which produce substances called metabolites which aside from the role in energy production are important in cell maintenance. Our particular interest is focused on a Krebs cycle enzyme called fumarate hydratase. Defects in fumerate hydratase cause high levels of metabolite fumarate to accumulate and this can have a drastic effect on cell metabolism.
How is this linked with the onset of cancer?
PP: There is no direct evidence to date linking fumarate accumulation with cancer, however we and others have shown the accumulation of fumarate has a significant effect on the ability of the cell to undergo metabolism. At present we are trying to characterise these changes. Some of these involve conferring a survival advantage upon cells and of course this can be directly linked to the progression of cancer.
What are the most important lines of research that have developed over the last five to ten years?
PP: Cancer research has being rapidly evolving over the last century starting with the biochemistry era followed by the genomic era where we saw a lot of cancer associated genes – tumour suppressor genes and oncogenes – identified. Recently the last five to ten years has seen a vast increase in metabolic studies of cancer and understanding how cancer cells produce their energy and have survival advantages. This has been facilitated by increases in technology including sensitivity of mass spectrometry and also the ability to label specific metabolites within cells and track these metabolites.
Why does your line of research matter, why should we put money into it?
PP: Kidney cancer only accounts for around 3% of all cancers. The kidney cancer we are working on which is associated with the specific genetic defects of fumerate hydratase is a highly aggressive form of kidney cancer. Actually when these cancers metastasize, spread throughout the body to date there are no effective therapies. We are hoping that by analysing the metabolism of these cancers and trying to elucidate the energy produced in pathways that they require, we can help design targets for therapy.
How does your research fit into Translational Medicine within the Department?
PP: Recently we identified the novel biomarker which is sensitive and specific enough to be used in the clinical setting and this is specifically to identify cancers with their specific genetic defects in fumerate hydratase. We have also created numerous models so we can study metabolism in greater detail, and we are hoping that these models might be applicable to other metabolic diseases which include diabetes and obesity.