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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 his 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.

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To achieve these aims, his laboratory 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. 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, including on-target toxicities, and have been extensively licenced to pharma industry for preclinical studies.

 

BV discovered the PI3Kdelta isoform of PI3K and with his team has 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 immunity, 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. Several inhibitors which differ in PI3K isoform-selectivity but share the ability to inhibit PI3Kδ are now approved for the treatment of specific B-cell malignancies.

 

Recent studies in collaboration with Klaus Okkenhaug, 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.

 

Current research is focused on the biology of the PI3Kalpha and PI3Kdelta isoforms, and on the role of the PTEN tumour suppressor, including novel ways to control the biological activities of these key PI3K pathway regulators.

 

BV is an elected member of EMBO and of the UK Academy of Medical Sciences.

 

Publications

  • PI3K inhibitors are finally coming of age
    Vanhaesebroeck B, Perry MWD, Brown JR, André F, Okkenhaug K. Nat Rev Drug Discov. 2021. 14.
  • PI3K isoforms in cell signalling and vesicle trafficking
    Benoit Bilanges, York Posor, Bart Vanhaesebroeck. Nat Rev Mol Cell Biol. 2019 Sep;20(9):515-534.
  • Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling.
    Berenjeno IM, Piñeiro R, Castillo SD, Pearce W, McGranahan N, Dewhurst SM, Meniel V, Birkbak NJ, Lau E, Sansregret L, Morelli D, Kanu N, Srinivas S, Graupera M, Parker VER, Montgomery KG, Moniz LS, Scudamore CL, Phillips WA, Semple RK, Clarke A, Swanton C, Vanhaesebroeck B. Nat Commun. 2017 Nov 24;8(1):1773.
  • Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism
    Bilanges B, Alliouachene S, Pearce W, Morelli D, Szabadkai G, Chung YL, Chicanne G, Valet C, Hill JM, Voshol PJ, Collinson L, Peddie C, Ali K, Ghazaly E, Rajeeve V, Trichas G, Srinivas S, Chaussade C, Salamon RS, Backer JM, Scudamore CL, Whitehead MA, Keaney EP, Murphy LO, Semple RK, Payrastre B, Tooze SA, Vanhaesebroeck B Nat Commun. 2017 Nov 27;8(1):1804.
  • Phosphoinositide 3-kinase: a new kid on the block in vascular anomalies.
    Castillo SD, Vanhaesebroeck B, Sebire NJ. J Pathol. 2016 Dec;240(4):387-396.
  • Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy
    Okkenhaug K, Graupera M, Vanhaesebroeck B. Cancer Discov. 2016. 6(10):1090-1105. 
  • Inactivation of class II PI3K-C2α induces leptin resistance, age-dependent insulin resistance and obesity in male mice
    Alliouachene S, Bilanges B, Chaussade C, Pearce W, Foukas LC, Scudamore CL, Moniz LS, Vanhaesebroeck B. Diabetologia. 2016 Jul;59(7):1503-12.
  • Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans
    Sandra D Castillo, Elena Tzouanacou, May Zaw-Thin, Inma M Berenjeno, Victoria E R Parker, Iñigo Chivite, Maria Milà-Guasch, Wayne Pearce, Isabelle Solomon, Ana Angulo-Urarte, Ana M Figueiredo, Robert E Dewhurst, Rachel G Knox, Graeme R Clark , Cheryl L Scudamore, Adam Badar, Tammy L Kalber, Julie Foster, Daniel J Stuckey, Anna L David , Wayne A Phillips, Mark F Lythgoe, Valerie Wilson, Robert K Semple, Neil J Sebire, Veronica A Kinsler, Mariona Graupera, Bart Vanhaesebroeck Sci Transl Med. 2016 Mar 30;8(332):332ra43.
  • Inactivation of the Class II PI3K-C2β Potentiates Insulin Signaling and Sensitivity
    Alliouachene S, Bilanges B, Chicanne G, Anderson KE, Pearce W, Ali K, Valet C, Posor Y, Low PC, Chaussade C, Scudamore CL, Salamon RS, Backer JM, Stephens L, Hawkins PT, Payrastre B, Vanhaesebroeck B. Cell Rep. 2015 Dec 1;13(9):1881-94.
  • Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer
    Ali K, Soond DR, Piñeiro R, Hagemann T, Pearce W, Lim EL, Bouabe H, Scudamore CL, Hancox T, Maecker H, Friedman L, Turner M, Okkenhaug K, Vanhaesebroeck B. Nature. 2014 Jun 19;509(7505):407-11.
  • Inhibition of the p110α isoform of PI 3-kinase stimulates nonfunctional tumor angiogenesis
    Soler A, Serra H, Pearce W, Angulo A, Guillermet-Guibert J, Friedman LS, Viñals F, Gerhardt H, Casanovas O, Graupera M, Vanhaesebroeck B. J Exp Med. 2013 Sep 23;210(10):1937-45.
  • Long-term p110α PI3K inactivation exerts a beneficial effect on metabolism.
    Foukas LC, Bilanges B, Bettedi L, Pearce W, Ali K, Sancho S, Withers DJ, Vanhaesebroeck B. EMBO Mol Med. 2013 Apr;5(4):563-71. 
  • The p110δ isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock.
    Aksoy E, Taboubi S, Torres D, Delbauve S, Hachani A, Whitehead MA, Pearce WP, Berenjeno-Martin I, Nock G, Filloux A, Beyaert R, Flamand V, Vanhaesebroeck B. Nature Immunol. 2012 Nov;13(11):1045-54.
  • The emerging mechanisms of isoform-specific PI3K signalling
    Bart Vanhaesebroeck, Julie Guillermet-Guibert, Mariona Graupera, Benoit Bilanges. Nat Rev Mol Cell Biol. 2010 May;11(5):329-41.
  • The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma
    Guillermet-Guibert J, Bjorklof K, Salpekar A, Gonella C, Ramadani F, Bilancio A, Meek S, Smith AJ, Okkenhaug K, Vanhaesebroeck B. Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8292-7. 
  • Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration.
    Graupera M, Guillermet-Guibert J, Foukas LC, Phng LK, Cain RJ, Salpekar A, Pearce W, Meek S, Millan J, Cutillas PR, Smith AJ, Ridley AJ, Ruhrberg C, Gerhardt H, Vanhaesebroeck B. Nature. 2008 May 29;453(7195):662-6.