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Pioneering a novel cancer targeting glyco-immunotherapy strategy


   MRC DiMeN Doctoral Training Partnership

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  Dr M A Fascione, Dr N Signoret, Prof Craig Robson  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Background: Human cells are coated in a thick layer of sticky sugars called the glycocalyx. Uniquely cancer cells are covered with an excess of the human ‘sialic acid’ sugar Neu5Ac, and this has been shown to ‘camouflage’ the cells from the immune system. However, 2 million years ago a hydroxylated form of this sugar known as Neu5Gc was also present on human cells, but evolutionary selection drove inactivation of the gene required for conversion of Neu5Ac to an ancestral sialic acid, and this resulted in the loss of the ancestral sugar from the surface of human cells. Following this selection event, humans have developed circulating antibodies against this sugar. 

Objectives: The aim of the project is to resurrect this ancestral sugar specifically in prostate cancer cells using antibody-targeted gene delivery. This strategy would aim to unleash the immune system’s existing antibodies to kill the cancer cells, constituting a completely novel approach to cancer immunotherapy. 

Experimental approach: Using novel chemical glyco-biology methods1,2 the student will contribute to the design of prostate cancer-cell specific gene delivery systems. The functional activity of these tools will be tested on well-established Prostate cancer (PCa) cell-lines, using a combination of flow cytometry, glycan mass spectrometry and immunofluorescence to determine the extent of cell surface glycan reengineering. Validation of the best delivery system will then follow using in vitro culture of primary prostate-isolated tumour cells and spheroids. This is a cross-disciplinary project primarily based at the University of York in the labs of Dr Martin Fascione (https://www.york.ac.uk/chemistry/staff/academic/d-g/mfascione/; Chemistry) and Dr Nathalie Signoret (https://www.york.ac.uk/biology/research/molecular-cellular-medicine/signoret/; Immunology, Hull York Medical School), and working collaboratively with Prof Craig Robson (https://www.ncl.ac.uk/medical-sciences/people/profile/cnrobson.html; Newcastle University Centre for Cancer). The student will train in aspects of organic chemistry, immunology and cancer cell biology specifically developing skills in glycoscience, protein bioconjugation, molecular biology, advanced cell imaging techniques and flow cytometry. The project would suit a candidate with an interest in translational science and any of chemical biology, glycoscience, immunology and/or cancer biology.

Novelty and Timeliness: In the last decade treatment of cancer has been revolutionised by antibody delivery of small molecule drugs and subsequently by cancer immunotherapy strategies which coopt the patient’s own immune system to fight the cancer. For the first time we aim to harness aspects of both these field defining strategies simultaneously through re-engineering of cell surface glycans.

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, York 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: https://www.dimen.org.uk/blog 

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

https://www.dimen.org.uk/how-to-apply 


Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover tuition fees, stipend and project costs. We also aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of full studentships to international applicants. Please read additional guidance here: https://www.dimen.org.uk/eligibility-criteria
Studentships commence: 1st October 2023
Good luck!

References

Keenan, T.; Spears, R.; Akkad, S., Mahon, C. S.; Hatton, N.; Walton, J.; Noble, A.; Yates, N.; Baumann, C. G.; Parkin, A.; Signoret, N. Y. M.; *Fascione, M. A. ‘A tale of two bioconjugations: pH controlled divergent reactivity of protein α-oxo aldehydes in competing α-oxo-Mannich and catalyst-free aldol ligations”. ACS. Chem. Biol., 2021, 16 (11), 2387-2400.
Yates, N. D; Akkad, S.; Noble, A.; Keenan, T.; Hatton, N.; *Signoret, N. Y. M.; *Fascione, M. A.
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