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

Summary of Project:

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 αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, α5β1, α8β1, and αIIbβ3, 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. 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 hypothesise that targeting multiple RGD-binding integrins will have a profoundly enhanced anticancer effect compared to single integrin-targeted agents by uniquely orchestrating:

  1. a direct anti-proliferative effect on integrin-expressing tumour tissue with inhibition of multiple redundant pathways promoting
  2. cell dissemination and,
  3. angiogenesis, through targeting tumour cell interactions with stromal and endothelial cells, and platelets.

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).

Funding:

Applicants will be expected to provide their own funding or external sponsorship. A bench fee of £10,000 will be applicable to this project, in addition to the tuition fees.

Supervisors:

Title and name:
Dr Helen Sheldrake
Position:
Lecturer in Organic and Medicinal Chemistry
Email address:
Telephone number :
Work+44 (0) 1274 236858
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