Tackling oxaliplatin drug resistance in colorectal cancer by developing a novel bifunctional prodrug

About the Project

Acquired drug resistance is a considerable problem for the treatment of colorectal cancer (CRC), of which oxaliplatin is a key component, with little improvement in the ~65% 5-year survival rate over the past 25 years. Modulation of resistance pathway component expression can maintain tumour drug sensitivity during multiple cycles of treatment, minimising chances of the tumour becoming resistant, and one would ideally want to administer the modulator specifically to the tumour at the same time as the drug. In preliminary cell-based studies we have identified compounds that can reduce resistance to oxaliplatin. We have previously demonstrated that a matrix-metalloproteinase 1 (MT1-MMP) activated peptide-based prodrug can differentially release a drug payload in a CRC xenograft model, and this prodrug platform has flexibility to be applied to other payloads.

Aim

To develop a bifunctional MT1-MMP-activated peptide prodrug which will minimise acquisition of resistance and improve efficacy of oxaliplatin in CRC patients.

Focus

Design and development of a prodrug incorporating oxaliplatin and a modulator of the resistance-causing survivin, LQZ-7I, with optimisation of formulation for intravenous administration. Following confirmation of differential tumour release in ex vivo studies, in vitro and in vivo proof-of-concept in CRC resistance models will be evaluated.

Who should apply

Applicants with a passion for medicinal and/or synthetic chemistry, and cancer drug discovery. Candidates should have, or expect to obtain, a first or good upper second-class degree (or non-UK equivalent) in a chemistry-based subject or an appropriate Master’s degree qualification. We are looking for applicants with evidence of laboratory experience in organic or medicinal chemistry (e.g. a significant research project), with some experience of drug analysis and/or cell-free or in vitro screening assays.

How to apply

Formal applications can be submitted via the University of Bradford web site; applicants will need to register an account, select 'Postgraduate Research' as the course and then use the keywords 'cancer therapeutics'. Applicants should then specify the project title in the 'Research Proposal' section.

Enquiries

For informal enquiries, please contact s.d.shnyder@bradford.ac.uk.

For further information about the Institute of Cancer Therapeutics Doctoral Training Centre, please contact r.a.falconer1@bradford.ac.uk, or take a look at our website.

Funding Notes

This is a self-funded PhD project; applicants will be expected to pay their own fees or have a suitable source of third-party funding. A bench fee of £10,000 per year may also apply to this project, in addition to the tuition fees. UK students may be able to apply for a Doctoral Loan from Student Finance for financial support.