Cell Signalling Research Group

Group Leader: Professor Bart Vanhaesebroeck, PhD FMedSci

Our research focuses on signalling by PI 3-kinases (PI3Ks), enzymes that are implicated in several human diseases or conditions, including cancer, overgrowth syndromes, inflammation and auto-immunity. The development of drugs to block PI3K action is actively pursued by the pharmaceutical industry.

Mammals have eight PI3K family members (are also known as isoforms). Our research aims to uncover the functions of PI3Ks in regulating cell behaviour, both in normal physiology and in disease, and to understand their molecular mechanism of action. 

PI3K in disease

A highlight of our work to date is the discovery of p110delta, a PI3K family member that is highly expressed in white blood cells, as a drug target in various diseases. Our team has been involved in the characterization of p110delta ‘all the way’, from gene cloning through to the generation of the first mouse models and the development of p110delta inhibitors (by PIramed UK, acquired by Roche in 2008). Over the years, we have uncovered p110delta as a drug target in immunity, inflammation and haematological malignancies and, most recently, as a target for cancer immunotherapy. In 2014, a p110delta inhibitor (Zydelig from Gilead Sciences) was the first PI3K inhibitor to be approved, namely for the treatment of specific blood cancers. p110delta inhibitors are also being trialled in arthritis and airway inflammation, and in solid tumours, the latter based on our most recent finding that p110delta inhibition leads to the activation of the immune system against cancer.

In order to delineate the roles of PI3K isoforms, we created the first ‘kinase-dead knockin’ mice. In these mice, a PI3K is inactivated by mutating a conserved ATP-binding amino acid in the active site of the kinase. This strategy, which preserves PI3K expression, provides a more adequate model for the effects of small molecule kinase inhibitors than classical gene knockout approaches. This approach allowed us to uncover roles of the p110alpha, p110beta and p110delta isoforms of class I PI3K in cells and mice. We have also employed this genetic strategy to target the class II and III PI3Ks and are in the process of characterising these mice and cells derived thereof.

PI3K isoforms

Our ambition is to repeat the success we had with p110delta. We continue to study class I PI3Ks, with an enhanced focus on cell-based studies to understand their molecular mechanism of action. We also aim to uncover the biological roles of the class II and III PI3K family members. We are also involved in efforts to develop drugs that modulate the PI3K pathway.

We welcome informal enquiries - if you would like to work with us, please contact Bart Vanhaesebroeck bart.vanh@ucl.ac.uk