title: Targeting tumour vasculature by inhibiting activin receptor-like kinase (ALK)1 function.
abstract: Angiogenesis is a hallmark of cancer and is now a validated therapeutic target in the clinical setting. Despite the initial success, anti-angiogenic compounds impinging on the vascular endothelial growth factor (VEGF) pathway display limited survival benefits in patients and resistance often develops due to activation of alternative pathways. Thus, finding and validating new targets is highly warranted. Activin receptor-like kinase (ALK)1 is a transforming growth factor beta (TGF-β) type I receptor predominantly expressed in actively proliferating endothelial cells (ECs). ALK1 has been shown to play a pivotal role in regulating angiogenesis by binding to bone morphogenetic protein (BMP)9 and 10. Two main pharmacological inhibitors, an ALK1-Fc fusion protein (Dalantercept/ACE-041) and a fully human antibody against the extracellular domain of ALK1 (PF-03446962) are currently under clinical development. Herein, we briefly recapitulate the role of ALK1 in blood vessel formation and the current status of the preclinical and clinical studies on inhibition of ALK1 signalling as an anti-angiogenic strategy. Future directions in terms of new combination regimens will also be presented.
authors.affiliation: Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, The Netherlands.
authors.forename: Amaya García
authors.initials: AG
authors.lastname: de Vinuesa
authors.affiliation: Department of Laboratory Medicine, Lund University, Medicon Village, SE-22381 Lund, Sweden.
authors.forename: Matteo
authors.initials: M
authors.lastname: Bocci
authors.affiliation: Department of Laboratory Medicine, Lund University, Medicon Village, SE-22381 Lund, Sweden kristian.pietras@med.lu.se p.ten_dijke@lumc.nl.
authors.forename: Kristian
authors.initials: K
authors.lastname: Pietras
authors.affiliation: Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, The Netherlands kristian.pietras@med.lu.se p.ten_dijke@lumc.nl.
authors.forename: Peter
authors.initials: P
authors.lastname: Ten Dijke
mesh_terms: D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; C575087:ascrinvacumab; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II
keywords: activin receptor-like kinase 1 (ALK1); angiogenesis; bone morphogenetic protein; tumour vasculature