Development of a test system for novel physiological MRI methodologies

One of the most deleterious diseases in the world. Early detection improves survival. Presently, cancer is detected, staged and followed-up most commonly by anatomical imaging, such as computed tomography (CT) and conventional magnetic resonance imaging (MRI).

Whilst metabolic changes are a hallmark of cancer and precede anatomical change, currently, there is a global lack of safe, cheap, easily accessible and accurate image-based metabolic evaluation techniques for cancer detection. Alterations in glucose metabolism are commonly found in cancer. Specifically, tumour cells preferentially take up glucose over normal cells, as they rely on enhanced aerobic glycolysis for their energy supply, a phenomenon known as the Warburg effect. Recently, we have exploited this finding through the use of a new radiation-free magnetic resonance imaging (MRI) technique, named glucose-based Chemical Exchange Saturation Transfer (GlucoCEST) (1). GlucoCEST has been shown to detect native glucose uptake in tumour models, yet the exact basis of the signal origin (is the signal only coming from extracellular space or can we measure any intracellular signal component) is still under debate, (1,2). Based on this original paper (1), we were able to raise a large EC grant aimed at bringing it from bench to bedside.

The problem with translation of this method to the clinics however lies in its inherent difficulties for such methods to be optimised within the clinical environment, and most preliminary experiments have been undertaken on animal models (1,2). In an attempt to refine, reduce and replace (3Rs) the use of animals, we propose here a PhD studentship for a biomedical engineer or student of equivalent background. The main task of this project will be to develop a series of bioreactors, available in sizes compatible with clinical MRI scanning, in a completely controlled environment, to help develop and refine imaging sequences for GlucoCEST and related MRI techniques. These bioreactors will be based on a temperature controlled, circulating concentrated yeast (S. cerevisiae) culture respiring on glucose. Respiratory behaviour of this yeast in bioreactor models is well-understood. Respiration on glucose results in a switch from aerobic to fermentative metabolism - equivalent to the Warburg effect in cancer cells - in this case converting the pyruvate product of glycolysis into ethanol rather than lactate. Existing mid-infrared optical methods can be used to detect glucose loss and ethanol formation in real time and UV/visible spectroscopy can be used to determine cell growth. This system will provide a quantitative metabolic system for real time calibration of the MRI methods used. Nobody has ever considered such phantoms so far, mainly because of the lack of metabolic MRI methods. Because the respiratory behaviour of yeast under such conditions is so well-established, this project is of relatively low-to-medium risk. It is however impossible to establish without the combined expertise from UCL (Dr Shonit Punwani, radiologist specialised in cancer imaging; Prof Peter Rich, biochemist specialised in spectroscopy and respiratory metabolism) and Gold Standard Phantoms (Prof Xavier Golay, CEO and MRI physicist).