Tumour Biology and Metastasis Team

Team Leader: Dr Suzanne Eccles

Location: McElwain Laboratories, Sutton

Section: Cancer Research UK Cancer Therapeutics Unit

Our research relates to the cellular processes involved in invasion and metastasis and their potential as therapeutic targets in cancer. We have a particular interest in glioma, prostate carcinoma and squamous carcinomas of the head and neck.  The molecular machinery of tumour cell invasion and neoangiogenesis has many common components, and may provide more selective (or additional) targets for therapeutic intervention compared with cell proliferation.  We have established a comprehensive panel of assays of in vitro and in vivo angiogenesis, invasion and metastasis for evaluation of novel inhibitors emerging from the Centre's drug discovery programme and other basic science and translational collaborations. In addition, we are exploring prognostic markers of tumour progression and pharmacodynamic indicators of response to treatment for translation to the clinic. 

We are focussing initially on selected targets for which there is evidence for a role in tumour angiogenesis and invasion, while in collaborative studies aiming to identify novel targets for future therapeutic exploitation. Specific examples follow. Hypoxia in tumours is a major inducer of neoangiogenesis and tumour progression, and PI3K pathway activation is one important intermediary in this response. Distinct PI3 kinases have been implicated in proliferation (p110α) and migration (p110β and δ) of leucocytes, but it is not known which isoforms are utilised by endothelial cells (or tumour cells) for these processes.  We have shown that selective inhibitors of certain PI3 kinase isoforms effectively block invasion and angiogenesis in vitro.  Future work will explore the role of the different PI3K isoforms in more detail (using RNAi approaches) and will take the most promising inhibitors through our test cascade into in vivo systems

Heat shock protein 90 (HSP90) chaperones a variety of key cellular proteins including ERB-B family members, steroid receptors, mutant p53 and signalling molecules. We have also shown that all major VEGF receptors are client proteins and that both geldanamycins and our novel HSP90 inhibitors have potent anti-angiogenic and anti-metastatic activity. We aim to determine if different pathways of tumour dissemination and colonisation are equally sensitive to inhibition and define the key client proteins involved. We are also collaborating on the pre-clinical development of inhibitors of Aurora kinase, PKB, CHK1 and CHK2 kinases with Centre colleagues.

Aims

• Understanding key signalling pathways in tumour and host cells which potentiate invasion and angiogenesis.
• Preclinical development of novel targeted therapies.

 

Find out more about:

• Evaluation of HSP90 as a Target in Tumour Progression and Angiogenesis
• PI3 Kinase Pathway in Tumour Angiogenesis and Metastasis
• Phospholipase Cγ as a Target for Therapy in Tumour Invasion and Angiogenesis
• Receptor Tyrosine Kinase (RTK) Inhibitors in Head and Neck Cancer
• Site-specific Determinants of Breast Cancer Metastasis
• Sigma-1 Receptor Biology