Bart Vanhaesebroeck (BV) is Professor of Cell Signalling at the UCL Cancer Institute, London.
Following a PhD in the Laboratory of Molecular Biology at Ghent University (Belgium), BV carried out postdoctoral studies at the Ludwig Institute for Cancer Research, London where he was involved in a systematic effort to isolate the genes encoding PI 3-kinases (PI3Ks). This led to the realisation that PI3Ks form a family of enzymes. Together with his colleagues, BV proposed the now universally-accepted classification and nomenclature of PI3K isoforms.
The aim of our laboratory is to uncover the function and mechanism of action of the PI3K isoforms in normal physiology and disease, and to support efforts to therapeutically interfere with this pathway.
To achieve these aims, we generated the first-ever ‘kinase knockin’ mice, in which a kinase is inactivated by germline mutation of a conserved ATP-binding residue in the kinase-active site (Science 2002:297:1031). This strategy provides a more adequate physiological model to study the effects of kinase-inhibitors compared to gene knock-out approaches. These mouse models have been highly predictive of PI3K-drug action in humans.
We discovered PI3Kdelta and have taken its characterization ‘all the way’, from gene-cloning, through to the development of the first mouse models, uncovering this PI3K as a new drug target in inflammation, allergy, haematological malignancies and, most recently, in solid tumours. This was followed by the generation of PI3Kdelta-inhibitors in a drug development programme with PIramed Ltd (acquired by Roche in 2008).
Targeting PI3Kdelta has been the most successful clinical PI3K-inhibitor development effort to date, culminating in the approval in 2014 of the PI3Kdelta-inhibitor idelasib/zydelig (Gilead) for the treatment of specific B-cell malignancies.
Our recent work (Nature 2014:510:407) indicates that PI3Kdelta-inhibition, through preferential inhibition of immunosuppressive regulatory T-cells, leads to immunostimulation in cancer, potentially widening the use of PI3Kdelta-inhibitors from haematological malignancies to solid tumours.
The concept of PI3Kdelta-inhibitor-driven cancer immunotherapy is currently being tested in various clinical trials. Evidence is emerging that this immunomodulatory role of PI3Kdelta is also key in its efficacy in haematological malignancies.
BV is an elected member of EMBO and of the UK Academy of Medical Sciences.