Simultaneous targeting of insulin-like growth factor-1 receptor and anaplastic lymphoma kinase in embryonal and alveolar rhabdomyosarcoma: A rational choice

• Published in: European journal of cancer (1990) Vol. 49; no. 16; pp. 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: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.11.2013; Elsevier
• 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; Netherlands; Anaplastic lymphoma kinase receptor; Insulin-like growth factor 1 receptor; Embryonal rhabdomyosarcoma; Targeted treatment; In vitro; Alveolar rhabdomyosarcoma; Choice; Targeting; Targeted therapy; Insulin-like growth factor; Insulin like growth factor; Cancerology; Type 1 insulin-like growth factor receptor; Targeted drug; rhabdomyosarcoma; Anaplastic lymphoma kinase; Protooncogene; Biological receptor; 1 receptor; Soft tissue sarcoma; Malignant tumor; Embryonal; Striated muscle disease; Treatment; C-Onc gene; Cancer
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2013.06.022

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.