title: Dual targeting of vascular endothelial growth factor and bone morphogenetic protein-9/10 impairs tumor growth through inhibition of angiogenesis.
abstract: Clinical development of anti-angiogenic agents has been a major landmark in cancer therapy for several types of cancers. Signals mediated by both vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP)-9 and 10 have been implicated in tumor angiogenesis. However, previous studies have shown that targeting the individual signals was not sufficiently effective in retarding tumor growth in certain preclinical and clinical conditions. In the present study, we developed a novel decoy chimeric receptor that traps both VEGF and BMP-9/10. Single targeting of either VEGF or BMP-9/10 signals significantly reduced the formation of tumor vessels in a mouse xenograft model of human pancreatic cancer; however, it did not show significant therapeutic effects on tumor growth. In contrast, dual targeting of the angiogenic signals resulted in more significant inhibition of tumor angiogenesis, leading to delay of tumor growth. Our findings suggest that simultaneous blockade of VEGF and BMP-9/10 signals is a promising therapeutic strategy for the cancers that are resistant to anti-VEGF and BMP-9/10 therapies.
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Oncology Team, Nanomedicine Group, Pharmaceutical Research Laboratories, Research and Development Group, Nippon Kayaku Co. Ltd., Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Akatsu
authors.affiliation: Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.|Department of Cellular Physiological Chemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yoshimatsu
authors.affiliation: Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Tomizawa
authors.affiliation: Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Katsura
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
authors.affiliation: Department of Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Watabe
mesh_terms: D030301:Activin Receptors, Type II / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D055427:Growth Differentiation Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D019485:Bone Morphogenetic Proteins; D055427:Growth Differentiation Factor 2; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II
keywords: ALK1; BMP-9/10; Fc-chimera; angiogenesis; vascular endothelial growth factor