title: Genomic and molecular characterization of malignant peripheral nerve sheath tumor identifies the IGF1R pathway as a primary target for treatment.
abstract: Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma that lacks effective therapeutic strategies. We gain insight into the most recurrent genetically altered pathways with the purpose of scanning possible therapeutic targets.
  
  
  
  We conducted a microarray-based comparative genomic hybridization profiling of two cohorts of primary MPNST tissue samples including 25 patients treated at The University of Texas MD Anderson Cancer Center and 26 patients from Tianjin Cancer Hospital. Immunohistochemistry (IHC) and cell biology detection and validation were carried out on human MPNST tissues and cell lines.
  
  
  
  Genomic characterization of 51 MPNST tissue samples identified several frequently amplified regions harboring 2,599 genes and regions of deletion including 4,901 genes. At the pathway level, we identified a significant enrichment of copy number-altering events in the insulin-like growth factor 1 receptor (IGF1R) pathway, including frequent amplifications of the IGF1R gene itself. To validate the IGF1R pathway as a potential target in MPNSTs, we first confirmed that high IGF1R protein correlated with worse tumor-free survival in an independent set of samples using IHC. Two MPNST cell lines (ST88-14 and STS26T) were used to determine the effect of attenuating IGF1R. Inhibition of IGF1R in ST88-14 cells using siRNAs or an IGF1R inhibitor, MK-0646, led to significant decreases in cell proliferation, invasion, and migration accompanied by attenuation of the PI3K/AKT and mitogen-activated protein kinase pathways.
  
  
  
  These integrated genomic and molecular studies provide evidence that the IGF1R pathway is a potential therapeutic target for patients with MPNST.
authors: Departments of Bone and Soft Tissue Tumor, Pathology, and Epidemiology and Biostatistics, Tianjin Medical University Cancer Hospital and Institute, Tianjin, China. jilongyang2003@yahoo.com.cn
authors: Jilong
authors: J
authors: Yang
authors: Antti
authors: A
authors: Ylipää
authors: Yan
authors: Y
authors: Sun
authors: Hong
authors: H
authors: Zheng
authors: Kexin
authors: K
authors: Chen
authors: Matti
authors: M
authors: Nykter
authors: Jonathan
authors: J
authors: Trent
authors: Nancy
authors: N
authors: Ratner
authors: Dina C
authors: DC
authors: Lev
authors: Wei
authors: W
authors: Zhang
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D059248:Chemoradiotherapy; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D023281:Genomics / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018317:Nerve Sheath Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D010524:Peripheral Nervous System Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D048049:Extracellular Signal-Regulated MAP Kinases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; C569480:dalotuzumab