Dual targeting of vascular endothelial growth factor and bone morphogenetic protein-9/10 impairs tumor growth through inhibition of angiogenesis

Cancer Sci. 2017 Jan;108(1):151-155. doi: 10.1111/cas.13103.

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.

Keywords: ALK1; BMP-9/10; Fc-chimera; angiogenesis; vascular endothelial growth factor.

Publication types

  • Validation Study

MeSH terms

  • Activin Receptors, Type II / chemistry
  • Activin Receptors, Type II / genetics
  • Activin Receptors, Type II / pharmacology
  • Activin Receptors, Type II / therapeutic use
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols*
  • Bone Morphogenetic Proteins / antagonists & inhibitors*
  • Bone Morphogenetic Proteins / metabolism
  • Cell Proliferation
  • Female
  • Growth Differentiation Factor 2 / antagonists & inhibitors
  • Growth Differentiation Factor 2 / metabolism
  • Humans
  • Immunoglobulin Fc Fragments / genetics
  • Immunoglobulin Fc Fragments / pharmacology
  • Immunoglobulin Fc Fragments / therapeutic use
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neovascularization, Pathologic / drug therapy*
  • Pancreatic Neoplasms / blood supply
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / pharmacology
  • Recombinant Fusion Proteins / therapeutic use
  • Signal Transduction / drug effects*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-1 / chemistry
  • Vascular Endothelial Growth Factor Receptor-1 / genetics
  • Vascular Endothelial Growth Factor Receptor-1 / pharmacology
  • Vascular Endothelial Growth Factor Receptor-1 / therapeutic use
  • Xenograft Model Antitumor Assays

Substances

  • Bone Morphogenetic Proteins
  • Growth Differentiation Factor 2
  • Immunoglobulin Fc Fragments
  • Recombinant Fusion Proteins
  • Vascular Endothelial Growth Factor A
  • FLT1 protein, human
  • Vascular Endothelial Growth Factor Receptor-1
  • ACVRL1 protein, human
  • Activin Receptors, Type II