Seminar

Recent discoveries on the roles of PI 3-kinase isoforms in cancer and beyond

Prof. Bart Vanhaesebroeck

Bart Vanhaesebroeck is Professor of Cell Signalling at the UCL Cancer Institute in London. Following a PhD from Ghent University (Belgium), focusing on cytokine signalling and cell death, I carried out postdoctoral studies with Mike Waterfield FRS, at the Ludwig Institute for Cancer Research, London where I was involved in the isolation of PI 3-kinase (PI3K) genes. These studies led to the realisation that PI3Ks form a family of related enzymes that are conserved in evolution. Our research aims to uncover the functions of these PI3K isoforms, both in normal physiology and in disease, to understand their molecular mechanism of action, and to develop Pi3K-based therapies in various disease contexts, with a focus on immunity and cancer. A highlight of our research is the discovery of the p110delta isoform of PI3K as a new drug target in inflammation, allergy, haematological malignancies and, most recently, in solid tumours. We have taken the characterization of p110delta ‘all the way’, from gene cloning, through to the development of the first mouse models, followed by the generation of p110delta inhibitors in a drug development programme with PIramed Ltd (purchased by Roche in 2008). Targeting p110delta has been the most successful clinical PI3K inhibitor development effort to date, which culminated in the approval in 2014 of the p110delta inhibitor Idelalisib/Zydelig (Gilead) for the treatment of specific blood cancers. p110delta inhibitors are also being trialled in arthritis and airway inflammation. Our recent work (Nature 2014:510:407) indicates that p110delta is also a target for immuno-stimulation in cancer, potentially widening the use of p110delta drugs to immune-therapy of solid tumours. We are in the process of testing this concept in Head and Neck cancer, in a collaboration with Cancer Research UK and Amgen. An increasing focus of the laboratory is to model the aberrant PI3K activation as observed in disease, using physiologically-relevant genetic strategies in mice and cells. A focus of this work is on the p110alpha isoform of PI3K, which is frequently overactive in cancer and overgrowth syndromes, as a consequence of the presence of activating point mutations. BV is an elected member of the EMBO (European Molecular Biology Organisation) and of the UK Academy of Medical Sciences.