The improved understanding of cancer biology provides opportunities for the development of molecular targeted therapies. Targets suitable for personalised medicine include several cytochromes P450 (CYPs) including CYP1A1, CYP1B1, CYP2S1 and CYP2W1, which have been shown to be over-expressed in tumour tissue and surrounding stroma compared to surrounding normal tissue. However, the potential of CYPs as a specific target in cancer chemotherapy remains hitherto unexplored. Our research is focussed on duocarmycin bioprecursor development with potential for clinical evaluation; two proof-of-concept studies have demonstrated the potential in targeting CYP1A1 in bladder cancer (Sutherland et al. Mol Cancer Ther 2013) and CYP2W1 in colorectal cancer tissues (Travica et al. Clin Cancer Res 2013). It is a multidisciplinary project and involves various scientific disciplines including medicinal chemistry, chemical biology, cancer biology and drug metabolism and pharmacokinetics (DMPK).
This project will focus on how various tumour models metabolise the duocarmycin bioprecursors when compared to normal tissue alone. The project will investigate the metabolism of potential bioprecursors by certain tumour specific cytochrome P450s (CYPs) and simultaneously characterise model systems for CYP isoform expression using various techniques including LC/MS/MS and UV. Further studies will monitor the activation and metabolism of compounds trying to identify these novel metabolites by sensitive mass spectrometry based methods. These studies will give a more comprehensive picture of the potential of using various CYPs as targets for therapeutic intervention.
At least 2:1 honours degree or equivalent. For full details of our entry requirements, please visit our website.