Cytochromes P450 in Cancer: Opportunities for Development of Personalised Medicine

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 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.