title: Targeting fibroblast growth factor receptor signaling inhibits prostate cancer progression.
abstract: OBJECTIVE
  Extensive correlative studies in human prostate cancer as well as studies in vitro and in mouse models indicate that fibroblast growth factor receptor (FGFR) signaling plays an important role in prostate cancer progression. In this study, we used a probe compound for an FGFR inhibitor, which potently inhibits FGFR-1-3 and significantly inhibits FGFR-4. The purpose of this study is to determine whether targeting FGFR signaling from all four FGFRs will have in vitro activities consistent with inhibition of tumor progression and will inhibit tumor progression in vivo.
  
  
  METHODS
  Effects of AZ8010 on FGFR signaling and invasion were analyzed using immortalized normal prostate epithelial (PNT1a) cells and PNT1a overexpressing FGFR-1 or FGFR-4. The effect of AZ8010 on invasion and proliferation in vitro was also evaluated in prostate cancer cell lines. Finally, the impact of AZ8010 on tumor progression in vivo was evaluated using a VCaP xenograft model.
  
  
  RESULTS
  AZ8010 completely inhibits FGFR-1 and significantly inhibits FGFR-4 signaling at 100 nmol/L, which is an achievable in vivo concentration. This results in marked inhibition of extracellular signal-regulated kinase (ERK) phosphorylation and invasion in PNT1a cells expressing FGFR-1 and FGFR-4 and all prostate cancer cell lines tested. Treatment in vivo completely inhibited VCaP tumor growth and significantly inhibited angiogenesis and proliferation and increased cell death in treated tumors. This was associated with marked inhibition of ERK phosphorylation in treated tumors.
  
  
  CONCLUSIONS
  Targeting FGFR signaling is a promising new approach to treating aggressive prostate cancer.
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Feng
authors.forename: Longjiang
authors.initials: L
authors.lastname: Shao
authors.forename: Wendong
authors.initials: W
authors.lastname: Yu
authors.forename: Paul
authors.initials: P
authors.lastname: Gavine
authors.forename: Michael
authors.initials: M
authors.lastname: Ittmann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics; D009389:Neovascularization, Pathologic; D011467:Prostate / Q000166:cytology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C496348:FGFR1 protein, human; C496371:FGFR4 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051499:Receptor, Fibroblast Growth Factor, Type 4; D048049:Extracellular Signal-Regulated MAP Kinases