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Cytochromes P450 in Cancer: Opportunities for Development of Personalised Medicine

Background of Project:

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). Two research projects are available:

Project 1:

This project is focussed on the discovery of new pharmacophores suitable for targeting CYPs overexpressed in cancer tissues. It includes synthesis of small molecules and assessment of their propensity for CYP-targeting using recombinant human CYPs and cancer cells lines proficient/deficient of target CYPs. Lead molecules generated from such studies will be assessed for the potential to be used in nanoparticle technology. Biotargeted nanoparticles have the potential to substantially improve the therapeutic index of duocarmycins by increasing drug potency via selective delivery to target cancer cells or tumor stroma, thereby reducing their systemic toxicity and undesired off-target effects. Similarly, similarly, CYP-targeting fluorescent chemical probes can also be designed with the purpose of being able to monitor tumour CYP expression compared to normal tissue in vivo, providing evidence of target tissue selectivity.

Project 2:

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.

Entry requirements:

Minimum 2:1 in a Bachelors degree in a relevant science discipline.

Supervisors:

Title and name:
Dr Klaus Pors
Position:
Senior Lecturer in Chemical Biology
Email address:
Telephone number :
Work+44 (0) 1274 236482
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Title and name:
Professor Paul Loadman
Position:
Chair of Drug Metabolism and Pharmacokinetics
Email address:
Telephone number :
Work+44 (0) 1274 233228
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Title and name:
Professor Anant Paradkar
Position:
Professor of Pharmaceutical Engineering Science
Email address:
Telephone number :
Work+44 (0) 1274 233900
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