1497P - Simultaneous Targeting of the Insulin-Like Growth Factor 1 Receptor (IGF-1R) and Anaplastic Lymphoma Kinase (ALK) in Embryonal and Alveolar Rhabdomyosarcoma

Abstract

ABSTRACT Introduction Rhabdomyosarcoma (RMS) is an aggressive soft tissue tumour that occurs predominantly in children and adolescents. Its two most common forms are embryonal (eRMS) and alveolar RMS (aRMS). Although survival has increased over the past decades after the introduction of multi-agent chemotherapy, the survival for the high-risk subpopulation remains poor (not exceeding 50%). Therefore, there is an urgent need for new systemic treatment options. The aim of the current study is to investigate the insulin-like growth factor-1 receptor (IGF-1R) and anaplastic lymphoma kinase (ALK) pathway as potential targets in RMS. Methods A total of 112 paraffin-embedded RMS tumor specimens (eRMS n = 86; aRMS n = 26) were collected on a tissue microarray. IGF-1R and ALK expression was evaluated by immunohistochemistry. A binary scoring system was used in which staining was scored positive when present in at least 10% of the tumour cells. The effect of the ALK small molecule inhibitor NVP-TAE684 (Novartis), the IGF-1R monoclonal antibody R1507 (Roche) and combined treatment was investigated by cytotoxicity assay MTT in four RMS cell lines (aRMS Rh30 and Rh41; eRMS Rh18 and RD). Results Expression of IGF-1R was seen in 72% of aRMS and 62% of eRMS, respectively. ALK expression was observed in 92% of aRMS and 39% of eRMS. Co-expression of IGF-1R and ALK was observed in 68% of aRMS and 32% of eRMS. In vitro, inhibition of the IGF-1R by R1507 resulted in diminished cell growth only in aRMS cell line Rh41 (IC50 11 ng/ml). NVP-TAE-684 resulted in diminished cell growth in aRMS cell lines Rh41 (IC50 103 nM) and Rh30 (IC50 211 nM), and to a lesser extent in eRMS cell lines Rh18 (IC50 585 nM) and RD (IC50 734nM). Simultaneous treatment could be assessed in aRMS cell line Rh41 by using different concentrations of R1507 and NVP-TAE684, and revealed a synergistic effect (combination index Conclusion In eRMS and in particular aRMS co-expression of IGF-1R and ALK is frequently detected. Cytotoxicity/growth arrest was increased with the combination of IGF-1R and ALK inhibition in vitro. The combination of ALK and IGF-1R inhibition in RMS seems promising and deserves further investigation. Disclosure All authors have declared no conflicts of interest.