Evaluation of HSP90 as a Target in Tumour Progression and Angiogenesis

Tumour Biology and Metastasis Team

Section: Cancer Research UK Cancer Therapeutics Unit

Heat shock protein 90 (HSP90) chaperones several key signalling molecules involved in tumour cell proliferation, invasion and angiogenesis, including ERB-B2, AKT, C-RAF, B-RAF (notably mutant forms), MET, eNOS and HIF-1a. 17AAG (an HSP90 inhibitor) potently inhibits the proliferation, motility and invasive potential of human tumour cells and activated endothelial cells. 17AAG also inhibits production of angiogenic growth factors. Unlike certain therapeutic modalities (notably radiotherapy and some cytotoxic agents) we have found that HSP90 inhibitors are equipotent under hypoxic and normoxic conditions.

We have identified novel endothelial cell-specific client proteins of the HSP90 chaperone, and have demonstrated their downregulation in response to treatment with 17AAG both in vitro and in vivo. Human tumour xenografts responding to HSP90 inhibitors have reduced vascularisation and metastasis is inhibited. HSP90 inhibitors may therefore have a useful role in cancer therapy by directly inhibiting tumour cell proliferation and invasion and also by blocking key steps in the angiogenic cascade which limit tumour expansion and dissemination. Novel HSP90 inhibitors discovered in collaboration with Winnersh, UK-based Vernalis (which show similar pluripotent therapeutic effects but have improved pharmacological properties) are now in preclinical development.