Investigation of antagonism of multiple RGD-binding integrins as a therapeutic strategy in advanced head and neck cancer

Background

The integrins are a family of transmembrane receptors which mediate cell-cell and cell-ECM adhesion, and signalling across the cell membrane involved in pathways controlling cell migration, proliferation, differentiation, cell survival and apoptosis. In cancers, their vital role in the cross-talk between the cell and extracellular matrix enhances the growth, migration, invasion and metastasis of cancer cells. The RGD-binding subfamily of integrins, comprising α_vβ₁, α_vβ₃, α_vβ₅, α_vβ₆, α_vβ₈, α₅β₁, α₈β₁, and α_IIbβ₃, are of particular interest, since there is strong evidence that their upregulation or ectopic expression on tumour tissues is correlated with tumour progression.

Simultaneous expression of multiple RGD-binding integrins has been observed in head and neck squamous cell carcinoma (HNSCC). Blocking one integrin increases expression of others which bind the same ligand, and can be unsuccessful at preventing cell spreading or migration, since tumour cells respond to inhibition of one or two integrins by using others to retain migration ability. We have identified that migration of a HNSCC cell line is promoted by some single integrin antagonists, but significantly reduced by combinations targeting 3-4 integrins. We hypothesise that targeting multiple RGD-binding integrins will have a profoundly enhanced anticancer effect compared to single integrin-targeted agents by uniquely orchestrating (a) a direct antiproliferative effect on integrin-expressing tumour tissue with inhibition of multiple redundant pathways promoting (b) cell dissemination and, (c) angiogenesis, through targeting tumour cell interactions with stromal and endothelial cells, and platelets. This project will build on our preliminary data to provide a robust basis for recommending multi-integrin targeted therapy as a treatment for HNSCC and identify the optimum combinations of integrin targets.

PhD Project objectives:

1. To contribute to our understanding of the expression and function of RGD-binding integrins in head and neck tumours using established cell lines and primary tissues
2. To investigate the effect of existing (singly targeted) and novel (multi-targeted) agents on the functional activity of these integrins with respect to cell adhesion, motility and processes associated with angiogenesis. 

This will involve identification of integrin expression on cell lines and tissue samples, and the use of cell-based techniques to investigate the effects and mechanisms of functional integrin inhibition in HNSCC.

Entry requirements:

At least 2:1 Honours degree in a relevant subject (preferably molecular biology, biochemistry, cancer biology etc).

How to apply

Formal applications can be made via the University of Bradford web site.