Abstract 3266: Cilengitide targets more efficiently pediatric than adult glioma cells in vitro through cell detachment and anoikis induction

Abstract

Abstract Despite the development of numerous clinical trials in pediatric cancers, the prognosis for children with high grade gliomas (HGG) remains poor, indicating a critical need for new treatments. Cilengitide (EMD 121974, Merck KgaA, Germany), a new compound in early phase clinical trial, is a selective antagonist of αvβ3 and αvβ5 integrins, known to be involved in tumor growth, angiogenesis and metastasis development. A previous hopeful study shown that Cilengitide is able to control the growth of tumor from adult glioblastoma U87MG xenografts through blood vessel growth inhibition [1]. The aim of our study was to evaluate, the direct efficiency of Cilengitide on pediatric glioma cell lines and to determine its mechanism of action in these specific glioma cells. For this study, we used a wide tumor cell panel including three high grade (SF188, KNS42, UW479) and two low grade (Res259, Res186) pediatric glioma cell lines compared to the prototypic adult HGG cell line U87MG. Flow cytometry analysis revealed various αVβ3 expression levels but no correlation with the tumor grade. As expected, the pediatric cell line UW479, which doesn't express αVβ3, presents no sensitivity to Cilengitide. All other pediatric cell lines, expressing αVβ3, are sensitive to Cilengitide. Interestingly, U87MG adult cells, which express a high αVβ3 protein level, are very slightly altered by Cilengitide. Thus we have demonstrated a higher cytotoxicity of Cilengitide in pediatric than in adult glioma cells. In addition, the presence of the target appears necessary but not sufficient for Cilengitide action. Cilengitide is a selective antagonist of integrins implicated in cell adhesion. Cell detachment assay have shown a rapid and dose dependant Cilengitide action in pediatric cell lines expressing αVβ3 as well as in adult cells which detach from their matrix after only 2h of treatment. However, this detachment is translated in a Cilengitide cytotoxicity in pediatric cell lines but not in adult cells that are able to growth in spite of the strong cell detachment induced by Cilengitide. Interestingly, growth kinetics in non adherent conditions, revealed that pediatric glioma cells were sensitive to anoikis and so died after Cilengitide-induced cell detachment. In contrast, adult glioma cells are able to form cells clusters and to resist to anoikis and thus to Cilengitide-induced detachment. In conclusion, Cilengitide action on glioma cells appears dependent of αVβ3 expression and sensitivity to anoikis, two properties found in the majority of pediatric cell lines. Thus Cilengitide is able to target directly and efficiently pediatric glioma cells in vitro. Future in vivo experiments should confirm these promising results in pediatric glioma orthotopic xenografts models. [1] Yamada et al., Effect of the angiogenesis inhibitor Cilengitide (EMD 121974) on glioblastoma growth in nude mice. Neurosurgery, 2006. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3266. doi:10.1158/1538-7445.AM2011-3266