Simultaneous Targeting of Insulin-Like Growth factor-1 Receptor and Anaplastic Lymphoma Kinase in Embryonal and Alveolar Rhabdomyosarcoma: A Rational Choice

Eur J Cancer. 2013 Nov;49(16):3462-70. doi: 10.1016/j.ejca.2013.06.022. Epub 2013 Jul 15.

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.

Patients and 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.

Conclusion: 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.

Keywords: Alveolar rhabdomyosarcoma; Anaplastic lymphoma kinase receptor; Embryonal rhabdomyosarcoma; In vitro; Insulin-like growth factor 1 receptor; Targeted treatment.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Anaplastic Lymphoma Kinase
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chi-Square Distribution
  • Child
  • Child, Preschool
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Humans
  • Infant
  • Infant, Newborn
  • Kaplan-Meier Estimate
  • Middle Aged
  • Molecular Targeted Therapy*
  • Netherlands
  • Protein Kinase Inhibitors / pharmacology
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptor, IGF Type 1 / antagonists & inhibitors*
  • Receptor, IGF Type 1 / metabolism
  • Rhabdomyosarcoma, Alveolar / drug therapy*
  • Rhabdomyosarcoma, Alveolar / enzymology
  • Rhabdomyosarcoma, Alveolar / mortality
  • Rhabdomyosarcoma, Alveolar / pathology
  • Rhabdomyosarcoma, Embryonal / drug therapy*
  • Rhabdomyosarcoma, Embryonal / enzymology
  • Rhabdomyosarcoma, Embryonal / mortality
  • Rhabdomyosarcoma, Embryonal / pathology
  • Young Adult

Substances

  • Protein Kinase Inhibitors
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases
  • Receptor, IGF Type 1