title: Activin Receptor-like Kinase 1 Ligand Trap Reduces Microvascular Density and Improves Chemotherapy Efficiency to Various Solid Tumors.
abstract: OBJECTIVE
  Antiangiogenic therapy, mostly targeting VEGF, has been applied in cancer patients for the last decade. However, resistance to anti-VEGF therapy and/or no significant benefit as monotherapeutic agent is often observed. Therefore, new antiangiogenic strategies are needed. In the current study, we investigated the therapeutic effect of interfering with the bone morphogenetic protein (BMP)9/activin receptor-like kinase (ALK)1 signaling pathway by using an ALK1-Fc ligand trap.
  
  
  METHODS
  We analyzed the potential antiangiogenic and antitumor effects of ALK1-Fc protein as monotherapy and in combination with chemotherapy in vivo in mouse models of melanoma, head and neck cancer, and invasive lobular breast carcinomas. ALK1-Fc sequesters BMP9 and 10 and prevents binding of these ligands to endothelial ALK1, which regulates angiogenesis.
  
  
  RESULTS
  Treatment of mice with ALK1-Fc strongly decreased the tumors' microvascular density in the three different mouse cancer models. However, this effect was not accompanied by a reduction in tumor volume. An immunohistochemical analysis of the tumor samples revealed that ALK1-Fc treatment increased the pericyte coverage of the remaining tumor vessels and decreased the hypoxia within the tumor. Next, we observed that combining ALK1-Fc with cisplatin inhibited tumor growth in the breast and head and neck cancer models more efficiently than chemotherapy alone.
  
  
  CONCLUSIONS
  The addition of ALK1-Fc to the cisplatin treatment was able to enhance the cytotoxic effect of the chemotherapy. Our results provide strong rationale to explore combined targeting of ALK1 with chemotherapy in a clinical setting, especially in the ongoing phase II clinical trials with ALK1-Fc.
authors.affiliation: Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, the Netherlands. Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Lukas J A C
authors.initials: LJ
authors.lastname: Hawinkels
authors.affiliation: Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Amaya Garcia
authors.initials: AG
authors.lastname: de Vinuesa
authors.affiliation: Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, the Netherlands. Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Madelon
authors.initials: M
authors.lastname: Paauwe
authors.affiliation: Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Marianna
authors.initials: M
authors.lastname: Kruithof-de Julio
authors.affiliation: Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Eliza
authors.initials: E
authors.lastname: Wiercinska
authors.affiliation: Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Pardali
authors.affiliation: Experimental Molecular Imaging group, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Mezzanotte
authors.affiliation: Experimental Molecular Imaging group, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Stijn
authors.initials: S
authors.lastname: Keereweer
authors.affiliation: Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Braumuller
authors.affiliation: Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Renier C
authors.initials: RC
authors.lastname: Heijkants
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.affiliation: Experimental Molecular Imaging group, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Clemens W
authors.initials: CW
authors.lastname: Löwik
authors.affiliation: Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Goumans
authors.affiliation: Department of Surgical Oncology, Laboratory of Experimental Surgical Oncology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Timo L
authors.initials: TL
authors.lastname: ten Hagen
authors.affiliation: Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, the Netherlands. Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden. p.ten_dijke@LUMC.nl.
authors.forename: Peter
authors.initials: P
authors.lastname: ten Dijke
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004357:Drug Synergism; D055427:Growth Differentiation Factor 2 / Q000378:metabolism; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; D055427:Growth Differentiation Factor 2; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; D053773:Transforming Growth Factor beta1; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II; C000591618:ALK1-Fc fusion protein, human