title: Prognostic and therapeutic relevance of the IGF pathway in Ewing's sarcoma patients.
abstract: The optimal target and timing of drugs interfering with the insulin-like growth factor (IGF) signaling system in Ewing's sarcoma (ES) remain undetermined. We examined the expression of IGF signaling proteins in ES samples taken before and after chemotherapy, and speculate about the optimal way of treating ES patients in the future. Tumor material (36 initial biopsies and 24 resection specimens after neoadjuvant chemotherapy) and follow-up data of 41 patients treated for ES at the Radboud University Nijmegen Medical Centre were analyzed. Immunohistochemical staining was done for IGF1, IGF2, IGFBP3, IGF-1R, phosphorylated AKT (pAKT), phosphorylated mTOR (pmTOR), and phosphorylated ERK (pERK), and staining intensity was scored semiquantitatively. Change of protein expression during treatment, correlations of effector cascade signaling, and influence on progression-free (PFS) and overall survival (OS) were tested. All potential targets were widely expressed at both time points. After chemotherapy, pmTOR expression decreased significantly (p = 0.021) while IGFBP3 increased (p = 0.005). Correlations exist between IGF-1R and pERK (ρ = 0.286, p = 0.031), IGF-1R and pAKT (ρ = 0.269, p = 0.045), pAKT and pERK (ρ = 0.460, p = 0.000), and pERK and pmTOR (ρ = 0.273, p = 0.038). In therapy-naive samples, combined expression of pAKT, pmTOR, and pERK predicted worse PFS (median, 11 vs. 32 months; p = 0.039) and OS (median, 18 vs. 83 months; p = 0.023). We identify an unfavorable prognostic group of ES patients with widely activated IGF-effector cascades, demonstrate cooperation between the different downstream pathways, and show how expression of IGF-related proteins may change after exposure to chemotherapy. These findings should be taken into account when designing future trials with IGF-targeting agents. We suggest the prospective exploration of chemotherapy and multi-target tyrosine kinase inhibitors in the first-line setting.
authors.affiliation: Department of Medical Oncology, Radboud University Medical Centre, Internal postal code 452, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: A C M
authors.initials: AC
authors.lastname: van de Luijtgaarden
authors.forename: Y M H
authors.initials: YM
authors.lastname: Versleijen-Jonkers
authors.forename: M H S
authors.initials: MH
authors.lastname: Roeffen
authors.forename: H W B
authors.initials: HW
authors.lastname: Schreuder
authors.forename: U E
authors.initials: UE
authors.lastname: Flucke
authors.forename: W T A
authors.initials: WT
authors.lastname: van der Graaf
mesh_terms: D000293:Adolescent; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008297:Male; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D013002:Somatomedins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; C546842:MTOR protein, human; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases