Research Interests

Discovery of inhibitors of SIAH function

The SIAH1 and 2 (Seven in Absentia Homologue) proteins are RING finger E3 ligases responsible for regulating levels of a number of important intracellular proteins via polyubiquitination and proteasomal degradation. This is a 3-step enzymatic process involving ubiquitin activation (E1) conjugation (E2) and ligation (E3). The latter step controls the specificity of the process, since E3 ligases recognise selective degradation signals (degrons) within their target substrates.

High throughput 3D tumour spheroid assays for target validation and drug evaluation

Standard 2D monolayer cultures used for target validation and drug screening studies do not adequately address the complexity of in vivo tumour pathophysiology. Although 3D spheroids better represent the cancer microenvironment (with gradients of proliferation, oxygenation and drug access) they have not been routinely used in high-throughput (HTS) mode. The aim of our studies is to develop a suite of in vitro 3D spheroid-based assays to rapidly and accurately quantify key aspects of the malignant phenotype:  growth, motility, invasion and angiogenesis and to deploy them in routine drug discovery projects.

The role of heat shock protein chaperones in tumour invasion and metastasis

Molecular chaperones such as HSP90 are responsible for the correct folding and localization of several key signalling molecules involved in tumour cell proliferation, invasion and angiogenesis, including ERB-B2, AKT, BRAF, CRAF, MET, eNOS, VEGFR and HIF-1alpha. We have shown that 17AAG and our novel HSP90 inhibitor NVP-AUY922 potently inhibit not only tumour cell proliferation, but also angiogenesis, invasion and metastasis in vitro and in vivo.  

Determinants of resistance of squamous carcinomas of the head and neck to targeted agents

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.