title: Simultaneous targeting of insulin-like growth factor-1 receptor and anaplastic lymphoma kinase in embryonal and alveolar rhabdomyosarcoma: a rational choice.
abstract: BACKGROUND
  Rhabdomyosarcoma (RMS) is an aggressive soft tissue tumour mainly affecting children and adolescents. Since survival of high-risk patients remains poor, new treatment options are awaited. The aim of this study is to investigate anaplastic lymphoma kinase (ALK) and insulin-like growth factor-1 receptor (IGF-1R) as potential therapeutic targets in RMS.
  
  
  METHODS
  One-hundred-and-twelve primary tumours (embryonal RMS (eRMS)86; alveolar RMS (aRMS)26) were collected. Expression of IGF-1R, ALK and downstream pathway proteins was evaluated by immunohistochemistry. The effect of ALK inhibitor NVP-TAE684 (Novartis), IGF-1R antibody R1507 (Roche) and combined treatment was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays in cell lines (aRMS Rh30, Rh41; eRMS Rh18, RD).
  
  
  RESULTS
  IGF-1R and ALK expression was observed in 72% and 92% of aRMS and 61% and 39% of eRMS, respectively. Co-expression was observed in 68% of aRMS and 32% of eRMS. Nuclear IGF-1R expression was an adverse prognostic factor in eRMS (5-year survival 46.9 ± 18.7% versus 84.4 ± 5.9%, p=0.006). In vitro, R1507 showed diminished viability predominantly in Rh41. NVP-TAE684 showed diminished viability in Rh41 and Rh30, and to a lesser extent in Rh18 and RD. Simultaneous treatment revealed synergistic activity against Rh41 and Rh30.
  
  
  CONCLUSIONS
  Co-expression of IGF-1R and ALK is detected in eRMS and particularly in aRMS. As combined inhibition reveals synergistic cytotoxic effects, this combination seems promising and needs further investigation.
authors.affiliation: Department of Medical Oncology, Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: J Carlijn
authors.initials: JC
authors.lastname: van Gaal
authors.forename: Melissa H S
authors.initials: MH
authors.lastname: Roeffen
authors.forename: Uta E
authors.initials: UE
authors.lastname: Flucke
authors.forename: Jeroen A W M
authors.initials: JA
authors.lastname: van der Laak
authors.forename: Gwen
authors.initials: G
authors.lastname: van der Heijden
authors.forename: Eveline S J M
authors.initials: ES
authors.lastname: de Bont
authors.forename: Albert J H
authors.initials: AJ
authors.lastname: Suurmeijer
authors.forename: Yvonne M H
authors.initials: YM
authors.lastname: Versleijen-Jonkers
authors.forename: Winette T A
authors.initials: WT
authors.lastname: van der Graaf
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009426:Netherlands; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018232:Rhabdomyosarcoma, Alveolar / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D018233:Rhabdomyosarcoma, Embryonal / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D055815:Young Adult
chemical_list: D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1
keywords: Alveolar rhabdomyosarcoma; Anaplastic lymphoma kinase receptor; Embryonal rhabdomyosarcoma; In vitro; Insulin-like growth factor 1 receptor; Targeted treatment