Research Interest
Determinants of resistance of squamous carcinomas of the head and neck to targeted agents
Sue Eccles, Carol Box, Miriam Zimmermann
Squamous cell carcinomas of the head and neck (SCCHN) initially respond well to major therapies, but recurrences are frequent and survival rates have improved little over the last decade. Surgery and radiotherapy have contributed to loco-regional tumour control and reduced morbidity, however, prevention or eradication of metastatic disease remains a challenge. Rationally selected, targeted therapies offer hope, but a great deal more research is required to identify patients likely to respond and to understand mechanisms of innate or acquired resistance. We have an established research programme with Dr Kevin Harrington, Mr Peter Rhŷs-Evans and Dr Chris Nutting (funded by the Oracle head and neck cancer charity).
Our objectives are to optimise the efficacy of molecularly targeted therapies by understanding features of SCCHN that determine their responses. To pursue these aims, we developed and characterised a panel of 30 SCCHN cell lines, (including 10 derived from RMH patients).
Standard 2D monolayer cultures used to assay tumour sensitivity to drugs lack microenvironmental complexity and may be poor predictors of in vivo efficacy. In addition, 3D environments and factors such as hypoxia may preferentially support cancer stem-like cells (CSCs), postulated to play a role in therapy-resistant recurrences.
Using flow cytometry-based assays, we have identified subpopulations of cells which exhibit characteristics of CSCs and are more resistant to drug treatment with (for example) HSP90 inhibitors. We are currently dissecting the underlying signaling pathways in these cell populations and investigating how microenvironmental factors impact their molecular profile.
Epidermal growth factor receptor (EGFR) is overexpressed in 80–100% of SCCHN and is an adverse, independent predictor for survival, yet clinical trials of EGFR tyrosine kinase inhibitors (TKIs) in SCCHN have yielded only modest response rates. We aim to elucidate molecular causes and effects of EGFR TKI resistance which may lead to the identification of new therapeutic targets or rational combinations of agents. To this end we have developed SCCHN models of acquired EGFR TKI resistance in vitro and in vivo and used them, together with array-based approaches, to identify a signature associated with TKI resistance.
The signature includes soluble proteins with previously ascribed roles in tumour progression, and has the potential for development as a non-invasive biomarker of response. Our resistant tumour models are being exploited in in vivo collaborations with Dr Simon Robinson (Division of Radiotherapy and Imaging) and with Dr Mounia Beloueche-Babari (Division of Radiotherapy and Imaging) to understand the significant changes in angiogenic, invasive and metabolic phenotypes we have discovered.
