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MRC DiMeN Doctoral Training Partnership: Development of prodrugs targeting DNA repair as novel anti-cancer therapeutics for neuroblastoma


MRC DiMeN Doctoral Training Partnership

Sheffield United Kingdom Biochemistry Cancer Biology Data Analysis Genetics Molecular Biology Pharmacology Statistics Toxicology

About the Project

Background: Neuroblastoma is the most common extra-cranial childhood cancer, with more than half of high-risk patients suffering relapse following initial treatment. Novel precision medicines are desperately required. The DNA Damage Response (DDR) plays an important role in neuroblastoma development and targeting DDR proteins such as ATR offers significant therapeutic potential but risks toxicity to non-cancerous tissues. To mitigate this, a novel prodrug of a potent ATR inhibitor activated by tumour-specific protease aminopeptidase-N has been developed by the secondary supervisor. This project focuses on evaluation and further development of this lead compound and will provide important insights into potential clinically useful drug combinations for neuroblastoma in the clinic. 

Aim: Quantitative assessment of prodrug activation in neuroblastoma cells to determine drug efficacy. The student will examine efficacy of combinations of prodrug with neuroblastoma frontline chemotherapies and ionising radiation. The biology work will inform the design of further developments of the lead compound.

Training: The student will be exposed to interdisciplinary training in biology and drug design in collaboration with our industry partner, to tackle one of the most devastating cancers in children. Techniques such as qPCR, Western blotting, comet assays and established DNA repair biochemical assays will be performed. The mechanism of action will be determined by interrogating predicted DNA repair pathways such as double-/single-strand break repair. Prodrug/active drug released in tumour/normal tissues ex vivo will be analysed using LCMS. 

Environment: The research will be carried out at the University of Sheffield and the Institute of Cancer Therapeutics, University of Bradford, where the latter houses labs for the Industry partner, Incanthera plc. Both groups benefit from a vibrant postgraduate research training environment, and the student will greatly benefit from the interdisciplinary nature of the project, fusing biology with medicinal chemistry and drug design.

Supervisor profiles, websites and social media: 

Sherif El-Khamisy: https://www.sheffield.ac.uk/biosciences/people/mbb-staff/academic/sherif-el-khamisy

Robert Falconer - https://www.bradford.ac.uk/staff/rafalconer1

Institute of Cancer Therapeutics: www.bradford.ac.uk/ict

Twitter: @SEK2016T, @rafalconer1, @ict_bradford

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme and how to apply can be found on our website:

https://bit.ly/3lQXR8A 


Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3.5yrs. Funding will cover UK tuition fees and stipend only. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: View Website
Studentships commence: 1st October 2021
Good luck!

References

1) Fielden J, Wiseman K, Torrecilla I,…El-Khamisy SF, Ramadan K (2020). TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts. Nature Communications, 11:1274.
2) Walker C, Herranz-Martin S…..El-Khamisy SF (2017). C9orf72 expansion disrupts ATM-mediated chromosomal break repair. Nature Neuroscience. 20: 1225-1235.
3) Mohanty, S.; Chen, Z.; Li, K.; Ribeiro Morais, G….Falconer, R.A.; Daldrup-Link, H.E. (2017). A novel theranostic strategy for MMP-14 expressing glioblastomas impacts survival. Molecular Cancer Therapeutics, 16:1909-1921.

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