title: Systemic analysis of gene expression profiles identifies ErbB3 as a potential drug target in pediatric alveolar rhabdomyosarcoma.
abstract: Pediatric sarcomas, including rhabdomyosarcomas, Ewing's sarcoma, and osteosarcoma, are aggressive tumors with poor survival rates. To overcome problems associated with nonselectivity of the current therapeutic approaches, targeted therapeutics have been developed. Currently, an increasing number of such drugs are used for treating malignancies of adult patients but little is known about their effects in pediatric patients. We analyzed expression of 24 clinically approved target genes in a wide variety of pediatric normal and malignant tissues using a novel high-throughput systems biology approach. Analysis of the Genesapiens database of human transcriptomes demonstrated statistically significant up-regulation of VEGFC and EPHA2 in Ewing's sarcoma, and ERBB3 in alveolar rhabdomyosarcomas. In silico data for ERBB3 was validated by demonstrating ErbB3 protein expression in pediatric rhabdomyosarcoma in vitro and in vivo. ERBB3 overexpression promoted whereas ERBB3-targeted siRNA suppressed rhabdomyosarcoma cell gowth, indicating a functional role for ErbB3 signaling in rhabdomyosarcoma. These data suggest that drugs targeting ErbB3, EphA2 or VEGF-C could be further tested as therapeutic targets for pediatric sarcomas.
authors.affiliation: Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.
authors.forename: Janne
authors.initials: J
authors.lastname: Nordberg
authors.forename: John Patrick
authors.initials: JP
authors.lastname: Mpindi
authors.forename: Kristiina
authors.initials: K
authors.lastname: Iljin
authors.forename: Arto Tapio
authors.initials: AT
authors.lastname: Pulliainen
authors.forename: Markku
authors.initials: M
authors.lastname: Kallajoki
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.forename: Klaus
authors.initials: K
authors.lastname: Elenius
authors.forename: Varpu
authors.initials: V
authors.lastname: Elenius
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002648:Child; D016000:Cluster Analysis; D017277:Drug Approval; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015203:Reproducibility of Results; D018232:Rhabdomyosarcoma, Alveolar / Q000188:drug therapy* / Q000235:genetics*; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D020893:Receptor, ErbB-3