Project No.2217

Primary Supervisor

Prof Michelle Garrett – University of Kent

Co-Supervisor(s)

Dr Jennifer Hiscock – University of Kent

Dr Tim Fenton – University of Southampton

Mr Sashi Kommuclinician – (Clinician and surgeon), Department of Urology, East Kent Hospitals University NHS Foundation Trust

Summary

Bladder cancer kills over 5,000 people per year with 10-year survival being less than 50%.

Treatment of bladder combines surgery with chemotherapy, in the form of mitomycin or gemcitabine delivered via catheter directly to the bladder. The effectiveness of these agents is limited by their ability to be taken up by bladder cancer cells and so there is a need to identify a new approach to solve this problem. Supramolecular Self-associating Amphiphiles (SSAs) are a new class of molecule invented by JH, and in collaboration with MG have been shown to act as enhancers of anticancer agent efficacy. This project will investigate the use of SSAs to increase the anticancer efficacy of mitomycin and gemcitabine and provide a route to a proof-of concept clinical trial for SSAs in bladder cancer.

Aims:
1. Synthesis of a selected set of SSA’s for analysis on bladder cancer cell lines.
2. Evaluate anticancer activity and membrane interactions of SSAs on bladder cancer cell lines.
3. Investigate potential correlations between gene expression (RNA Seq) of bladder cancer cell lines with SSA activity.

This is a multidisciplinary chemical biology project where the student will spend time in the Hiscock lab designing and synthesising SSAs and the analysing their physicochemical effects. The student will also perform patch clamp, membrane fluidity and vesicle leakage experiments to ascertain SSA interaction with model cell membranes (Aims 1, 2). In the Garrett lab the student will then evaluate the cellular cytotoxicity of the SSAs alone and in combination with mitomycin and gemcitabine on bladder a cancer cell line panel followed by detailed cell membrane interaction studies including confocal microscopy and electron microscopy (Aim 2). RNA sequencing of bladder cancer cell lines will then be done and the results analysed in the Fenton lab, to investigate correlation of gene expression patterns with SSA effects i.e. enzymes that alter membrane composition (Aim 3). Clinical expertise in bladder cancer will be provided by Mr Sashi Kommu (clinician/surgeon) who will provide line of sight for the project to the clinic.

For more information please contact m.d.garrett@kent.ac.uk