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

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• 作者：J. Carlijn van Gaal ; Melissa H.S. Roeffen ; Uta E. Flucke ; Jeroen A.W.M. van der Laak ; Gwen van der Heijden ; Eveline S.J.M. de Bont ; Albert J.H. Suurmeijer ; Yvonne M.H. Versleijen-Jonkers ; Winette T.A. van der Graaf
• 关键词：Alveolar rhabdomyosarcoma ; Anaplastic lymphoma kinase receptor ; Embryonal rhabdomyosarcoma ; Insulin-like growth factor 1 receptor ; In vitro ; Targeted treatment
• 刊名：European Journal of Cancer
• 出版年：2013
• 出版时间：November, 2013
• 年：2013
• 卷：49
• 期：16
• 页码：3462-3470
• 全文大小：1164 K

文摘

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 ¡À 18.7 % versus 84.4 ¡À 5.9 % , m>pm> = 0.006). m>In vitrom>, 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.