Scientific background
This project targets the current gap in therapeutic approaches targeting Triple Negative Breast Cancer (TNBC) that, unlike other breast cancer subtypes, lacks recommended chemotherapy treatment.
Recent studies suggest that Nectin-4 is a promising target for the treatment of TNBC. Nectin-4 is expressed during foetal development, with expression declining in adult life, and it is re-expressed as a tumour-associated antigen with pro-oncogenic properties in TNBC and other cancers, including Bladder Cancer and Lung Cancer. Thus, Nectin-4 is both a promising new prognostic biomarker and specific therapeutic target for the treatment of TNBC.
Studies on patient samples show that Nectin-4 is highly expressed in cancer tissues, but is not detectable in healthy ones. The hypothesis is that targeting Nectin-4 with a peptide conjugated with toxin could provide a novel treatment for TNBC.
Novel compounds designed at our collaborators – Bicycle Therapeutics - are targeting Nectin-4 specifically at nanomolar range and can potentially be used as homing devices, having shown success in in vitro cell assays. However their mechanism of action and exact domain tropism is unknown.
Research methodology
In collaboration with Bicycle Therapeutics, we aim to solve the crystal structure of the extracellular domain of Nectin-4 bound to these proprietary cyclic peptides, which will guide further optimisation of the peptide before preclinical and clinical studies.
Training
The student will express and purify recombinant proteins using bacterial expression system. The student will produce protein crystals suitable for investigation using X-Ray crystallography with the aim of solving the structure of the Nectin-4 extracellular domain bound to different bicycle peptides provided by Bicycle Therapeutics.
In addition to hands-on practical research skills at University of Essex, the student will attend the Diamond Light Source BAG training courses and participate in data collection and processing.
This project is highly interdisciplinary and involves a high-profile industrial collaboration, plus the student will benefit from an international environment in close contact with two PhD students and two PDRA engaged in related drug discovery projects.
Furthermore, if successful, this highly translational research has the potential to lead to a 3-year PhD scholarship.
