Document Detail

Prognostic and therapeutic relevance of the IGF pathway in Ewing's sarcoma patients.
MedLine Citation:
PMID:  23292309     Owner:  NLM     Status:  Publisher    
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.
A C M van de Luijtgaarden; Y M H Versleijen-Jonkers; M H S Roeffen; H W B Schreuder; U E Flucke; W T A van der Graaf
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-6
Journal Detail:
Title:  Targeted oncology     Volume:  -     ISSN:  1776-260X     ISO Abbreviation:  Target Oncol     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-7     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101270595     Medline TA:  Target Oncol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Department of Medical Oncology, Radboud University Medical Centre, Internal postal code 452, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
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