title: Placental growth factor upregulation is a host response to antiangiogenic therapy.
abstract: OBJECTIVE
  Placental growth factor (PlGF) is an angiogenic protein. Upregulation of PlGF has been observed in the clinic following antiangiogenic regimens targeting the VEGF pathway. PlGF has been proposed as a therapeutic target for oncology. sFLT01 is a novel fusion protein that neutralizes mouse and human PlGF (mPlGF, hPlGF) and mouse and human VEGF-A (mVEGF-A, hVEGF-A). It was tested in syngeneic and xenograft tumor models to evaluate the effects of simultaneously neutralizing PlGF and VEGF-A and to investigate changes observed in the clinic in preclinical models.
  
  
  METHODS
  Production of PlGF and VEGF-A by B16F10 and A673 cancer cells in vitro was assessed. Mice with subcutaneous B16F10 melanoma or A673 sarcoma tumors were treated with sFLT01. Tumor volumes and microvessel density (MVD) were measured to assess efficacy. Serum levels of hVEGF-A, hPlGF, and mPlGF at early and late time points were determined by ELISA.
  
  
  RESULTS
  Exposure of cancer cell lines to sFLT01 caused a decrease in VEGF secretion. sFLT01 inhibited tumor growth, prolonged survival, and decreased MVD. Analysis of serum collected from treated mice showed that sFLT01 administration caused a marked increase in circulating mPlGF but not hPlGF or hVEGF. sFLT01 treatment also increased circulating mPlGF levels in non-tumor-bearing mice.
  
  
  CONCLUSIONS
  With the tumor cell lines and mouse models we used, antiangiogenic therapies that target both PlGF and VEGF may elicit a host response rather than, or in addition to, a malignant cell response that contribute to therapeutic resistance and tumor escape as suggested by others.
authors.affiliation: Genzyme Corporation, Framingham, Massachusetts 01701, USA. rebecca.bagley@genzyme.com
authors.forename: Rebecca G
authors.initials: RG
authors.lastname: Bagley
authors.forename: Yi
authors.initials: Y
authors.lastname: Ren
authors.forename: William
authors.initials: W
authors.lastname: Weber
authors.forename: Min
authors.initials: M
authors.lastname: Yao
authors.forename: Leslie
authors.initials: L
authors.lastname: Kurtzberg
authors.forename: Jason
authors.initials: J
authors.lastname: Pinckney
authors.forename: Dinesh
authors.initials: D
authors.lastname: Bangari
authors.forename: Cokey
authors.initials: C
authors.lastname: Nguyen
authors.forename: William
authors.initials: W
authors.lastname: Brondyk
authors.forename: Johanne
authors.initials: J
authors.lastname: Kaplan
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Teicher
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000037:antagonists & inhibitors / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D020533:Angiogenesis Inhibitors; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1