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 gr...

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Published in:European journal of cancer (1990) 2013-11, Vol.49 (16), p.3462-3470
Main Authors: van Gaal, J. Carlijn, Roeffen, Melissa H.S, Flucke, Uta E, van der Laak, Jeroen A.W.M, van der Heijden, Gwen, de Bont, Eveline S.J.M, Suurmeijer, Albert J.H, Versleijen-Jonkers, Yvonne M.H, van der Graaf, Winette T.A
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Alveolar rhabdomyosarcoma
Anaplastic lymphoma kinase receptor
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Biological and medical sciences
Cell Line, Tumor
Cell Survival - drug effects
Chi-Square Distribution
Child
Child, Preschool
Dose-Response Relationship, Drug
Drug Synergism
Embryonal rhabdomyosarcoma
Hematology, Oncology and Palliative Medicine
Humans
In vitro
Infant
Infant, Newborn
Insulin-like growth factor 1 receptor
Kaplan-Meier Estimate
Medical sciences
Middle Aged
Molecular Targeted Therapy
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Netherlands
Pharmacology. Drug treatments
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
Targeted treatment
Tumors
Young Adult
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Summary: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.
ISSN:0959-8049
1879-0852
DOI:10.1016/j.ejca.2013.06.022