title: Investigation of the insulin-like growth factor-1 signaling pathway in localized Ewing sarcoma: a report from the Children's Oncology Group.
abstract: BACKGROUND
  The insulin-like growth factor-1 (IGF-1) signaling pathway plays an important role in the pathology of Ewing sarcoma (ES). Retrospective studies have suggested that levels of IGF-1 and IGF binding protein 3 (IGFBP-3) are correlated with the outcome of patients with ES.
  
  
  METHODS
  The IGF-1 signaling pathway was investigated prospectively in 269 patients who had localized, previously untreated ES. Serum samples were obtained at diagnosis, and concentrations of IGF-1 and IGFBP-3 were determined by enzyme-linked immunosorbent assays. In addition, immunohistochemistry (IHC) was performed to assay for phosphorylated p70S6 kinase, protein kinase B (Akt), and forkhead box protein O1 (FOXO1) and to determine the presence of protein tyrosine phosphatase-L1 (PTPL1). IHC findings along with IGF-1 and IGFBP-3 concentrations were correlated with age, tumor location, sex, event-free survival, and overall survival.
  
  
  RESULTS
  Patients aged >18 years tended to have higher levels of IGF-1 (P = .10), lower levels of IGFBP-3 (P = .16), and decreased IGFBP-3:IGF-1 ratios (P = .01). No correlations were observed between sex, tumor location, or outcomes and concentrations of IGF-1 or IGFBP-3. Phosphorylation of p70S6 kinase, Akt, and FOXO1 was detected in the majority of patient tissues but was not associated with age, sex, or tumor location. PTPL1 was present in >80% of tumors and also was not correlated with age, sex, or tumor location. There was no difference in survival with respect to the presence of phosphorylated p70S6 kinase, phosphorylated FOXO1, phosphorylated Akt, or PTPL1.
  
  
  CONCLUSIONS
  The baseline IGFBP-3:IGF-1 ratio was correlated with age but did not affect the outcomes of patients with ES. The authors concluded that additional investigation of the IGF-1 pathway is warranted in patients with ES, and especially in those who have received treatment with IGF-1 receptor antibody inhibitors.
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology/Oncology, Vanderbilt University, Nashville, Tennessee 20057-1469, USA.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Borinstein
authors.forename: Donald A
authors.initials: DA
authors.lastname: Barkauskas
authors.forename: Mark
authors.initials: M
authors.lastname: Krailo
authors.forename: Daniel
authors.initials: D
authors.lastname: Scher
authors.forename: Lauren
authors.initials: L
authors.lastname: Scher
authors.forename: Silke
authors.initials: S
authors.lastname: Schlottmann
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Kallakury
authors.forename: Paul S
authors.initials: PS
authors.lastname: Dickman
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Pawel
authors.forename: Daniel C
authors.initials: DC
authors.lastname: West
authors.forename: Richard B
authors.initials: RB
authors.lastname: Womer
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Toretsky
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D002648:Child; D005260:Female; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D012512:Sarcoma, Ewing / Q000097:blood* / Q000401:mortality; D015398:Signal Transduction
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I