title: Targeting activin receptor-like kinase 1 inhibits angiogenesis and tumorigenesis through a mechanism of action complementary to anti-VEGF therapies.
abstract: Genetic and molecular studies suggest that activin receptor-like kinase 1 (ALK1) plays an important role in vascular development, remodeling, and pathologic angiogenesis. Here we investigated the role of ALK1 in angiogenesis in the context of common proangiogenic factors [PAF; VEGF-A and basic fibroblast growth factor (bFGF)]. We observed that PAFs stimulated ALK1-mediated signaling, including Smad1/5/8 phosphorylation, nuclear translocation and Id-1 expression, cell spreading, and tubulogenesis of endothelial cells (EC). An antibody specifically targeting ALK1 (anti-ALK1) markedly inhibited these events. In mice, anti-ALK1 suppressed Matrigel angiogenesis stimulated by PAFs and inhibited xenograft tumor growth by attenuating both blood and lymphatic vessel angiogenesis. In a human melanoma model with acquired resistance to a VEGF receptor kinase inhibitor, anti-ALK1 also delayed tumor growth and disturbed vascular normalization associated with VEGF receptor inhibition. In a human/mouse chimera tumor model, targeting human ALK1 decreased human vessel density and improved antitumor efficacy when combined with bevacizumab (anti-VEGF). Antiangiogenesis and antitumor efficacy were associated with disrupted co-localization of ECs with desmin(+) perivascular cells, and reduction of blood flow primarily in large/mature vessels as assessed by contrast-enhanced ultrasonography. Thus, ALK1 may play a role in stabilizing angiogenic vessels and contribute to resistance to anti-VEGF therapies. Given our observation of its expression in the vasculature of many human tumor types and in circulating ECs from patients with advanced cancers, ALK1 blockade may represent an effective therapeutic opportunity complementary to the current antiangiogenic modalities in the clinic.
authors.affiliation: Oncology Research Unit, Drug Safety, Research, and Development, and Translational Oncology, Pfizer Inc., San Diego, California, USA. dana.hu-lowe@pfizer.com
authors.forename: Dana D
authors.initials: DD
authors.lastname: Hu-Lowe
authors.forename: Enhong
authors.initials: E
authors.lastname: Chen
authors.forename: Lianglin
authors.initials: L
authors.lastname: Zhang
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Watson
authors.forename: Patrizia
authors.initials: P
authors.lastname: Mancuso
authors.forename: Patrick
authors.initials: P
authors.lastname: Lappin
authors.forename: Grant
authors.initials: G
authors.lastname: Wickman
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Chen
authors.forename: Jianying
authors.initials: J
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Jiang
authors.forename: Karin
authors.initials: K
authors.lastname: Amundson
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.forename: Andreas
authors.initials: A
authors.lastname: Erbersdobler
authors.forename: Simon
authors.initials: S
authors.lastname: Bergqvist
authors.forename: Zheng
authors.initials: Z
authors.lastname: Feng
authors.forename: Terri A
authors.initials: TA
authors.lastname: Swanson
authors.forename: Brett H
authors.initials: BH
authors.lastname: Simmons
authors.forename: John
authors.initials: J
authors.lastname: Lippincott
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Casperson
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Levin
authors.forename: Corrado Gallo
authors.initials: CG
authors.lastname: Stampino
authors.forename: David R
authors.initials: DR
authors.lastname: Shalinsky
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Ferrara
authors.forename: Walter
authors.initials: W
authors.lastname: Fiedler
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertolini
mesh_terms: D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors*; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II