Resurrecting ancestral human sugars: a novel ‘molecular archaeology’ approach to cancer immunotherapy using chemical bioconjugation

Background
Human cells surfaces are coated in a thick layer of sticky sugars called the glycocalyx. The composition of this coating is dynamic and changes depending on cell type and function. Uniquely cancer cells are covered with an excess of the human sialic acid sugar Neu5Ac, and this hypersialylation has been shown to ‘camouflage’ the cell from the immune system cancer, specifically NK (natural killer) cell cytotoxicity. However over 2 million years ago, Neu5Ac was not the only sialic acid sugar present on human cell surfaces, a hydroxylated form of the sugar known as Neu5Gc was also present, but evolutionary selection drove inactivation of a CMAH hydroxylase gene required in conversion of Neu5ac to Neu5Gc, and this resulted in the loss of the ancestral sugar from the surface of human cells.

Aims
Following this selection event, humans have developed circulating anti-Neu5Gc IgG antibodies making this sugar antigenic. Our aim is to resurrect this ancestral sugar specifically in bladder cancer cells, using antibody-targeted gene delivery to trigger in vivo reengineering of the modern day human cell surface Neu5Ac. This strategy would aim to unleash the immune system’s existing anti-Neu5Gc antibodies to initiate a response via antibody-dependant cellular cytotoxicity (ADCC), constituting a completely novel approach to cancer immunotherapy.

All research students follow our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills. All research students take the core training package which provides both a grounding in the skills required for their research, and transferable skills to enhance employability opportunities following graduation. Core training is progressive and takes place at appropriate points throughout a student’s higher degree programme, with the majority of training taking place in Year 1. In conjunction with the Core training, students, in consultation with their supervisor(s), select training related to the area of their research.

Chemical and molecular biology training and synthetic expertise will be passed on from the Fascione group, since this project will make use of novel bio-orthogonal methodologies and unnatural amino acids which have been developed and patented within the group. Training would be provided by a PDRA appointed to a concurrent EPSRC grant running across all three groups. The Davies group will provide specific training in protein expression and mamallian construct design through existing PDRAs and research staff. The Southgate group will provide training in the culture and study of bladder cancer cells through existing full time permanent research technicians embedded within the Jack Birch Unit.

The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel: https://www.york.ac.uk/chemistry/ed/. This PhD project is available to study full-time or part-time (50%).

This PhD will formally start on 1 October 2019. Induction activities will start on 30 September.