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.

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.

• Authors: 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
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 49 Issue 16 Pg. 3462-70 (Nov 2013) ISSN: 1879-0852 [Electronic] England
• PMID: 23867124 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

• 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, metabolism)
• Receptor, IGF Type 1 (antagonists & inhibitors, metabolism)
• Rhabdomyosarcoma, Alveolar (drug therapy, enzymology, mortality, pathology)
• Rhabdomyosarcoma, Embryonal (drug therapy, enzymology, mortality, pathology)
• Young Adult