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Cancers 2019, 11(3), 359; https://doi.org/10.3390/cancers11030359

The Small Molecule Ephrin Receptor Inhibitor, GLPG1790, Reduces Renewal Capabilities of Cancer Stem Cells, Showing Anti-Tumour Efficacy on Preclinical Glioblastoma Models

1
Division of Radiation Oncology, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Via Vetoio (Coppito II), 67100 L’Aquila, Italy
2
Laboratory of Radiobiology, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Via Vetoio (Coppito II), 67100 L’Aquila, Italy
3
Laboratory of cellular pathology, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Via Vetoio 1 (Coppito II), 67100 L’Aquila, Italy
4
Laboratory of Human Anatomy; Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Via Vetoio (Coppito II), 67100 L’Aquila, Italy
5
Laboratory of Neurophysiology, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Via Vetoio (Coppito II), 67100 L’Aquila, Italy
6
Department of Life, Health and Environmental Sciences, University of L’Aquila, Via Vetoio (Coppito II), 67100 L’Aquila, Italy
7
Laboratory of Experimental Medicine and Environmental Pathology, University Hub “Sabina Universitas”, 02100 Rieti, Italy
8
Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, 00161 Rome, Italy
9
Galapagos NV, Industriepark Mechelen Noord, General De Wittelaan L11 A3, 2880 Mechelen, Belgium
10
Galapagos SASU, 102 avenue Gaston Roussel, 93230 Romainville, France
*
Author to whom correspondence should be addressed.
Received: 8 January 2019 / Revised: 4 March 2019 / Accepted: 5 March 2019 / Published: 13 March 2019
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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Abstract

Therapies against glioblastoma (GBM) show a high percentage of failure associated with the survival of glioma stem cells (GSCs) that repopulate treated tumours. Forced differentiation of GSCs is a promising new approach in cancer treatment. Erythropoietin-producing hepatocellular (Eph) receptors drive tumourigenicity and stemness in GBM. We tested GLPG1790, a first small molecule with inhibition activity versus inhibitor of various Eph receptor kinases, in preclinical GBM models using in vitro and in vivo assays. GLPG1790 rapidly and persistently inhibited Ephrin-A1-mediated phosphorylation of Tyr588 and Ser897, completely blocking EphA2 receptor signalling. Similarly, this compound blocks the ephrin B2-mediated EphA3 and EphB4 tyrosine phosphorylation. This resulted in anti-glioma effects. GLPG1790 down-modulated the expression of mesenchymal markers CD44, Sox2, nestin, octamer-binding transcription factor 3/4 (Oct3/4), Nanog, CD90, and CD105, and up-regulated that of glial fibrillary acidic protein (GFAP) and pro-neural/neuronal markers, βIII tubulin, and neurofilaments. GLPG1790 reduced tumour growth in vivo. These effects were larger compared to radiation therapy (RT; U251 and T98G xenografts) and smaller than those of temozolomide (TMZ; U251 and U87MG cell models). By contrast, GLPG1790 showed effects that were higher than Radiotherapy (RT) and similar to Temozolomide (TMZ) in orthotopic U87MG and CSCs-5 models in terms of disease-free survival (DFS) and overall survival (OS). Further experiments were necessary to study possible interactions with radio- and chemotherapy. GLPG1790 demonstrated anti-tumor effects regulating both the differentiative status of Glioma Initiating Cells (GICs) and the quality of tumor microenvironment, translating into efficacy in aggressive GBM mouse models. Significant common molecular targets to radio and chemo therapy supported the combination use of GLPG1790 in ameliorative antiglioma therapy. View Full-Text
Keywords: glioblastoma; ephrin system; glioma stem like cells glioblastoma; ephrin system; glioma stem like cells
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Gravina, G.L.; Mancini, A.; Colapietro, A.; Delle Monache, S.; Sferra, R.; Vitale, F.; Cristiano, L.; Martellucci, S.; Marampon, F.; Mattei, V.; Beirinckx, F.; Pujuguet, P.; Saniere, L.; Lorenzon, G.; van der Aar, E.; Festuccia, C. The Small Molecule Ephrin Receptor Inhibitor, GLPG1790, Reduces Renewal Capabilities of Cancer Stem Cells, Showing Anti-Tumour Efficacy on Preclinical Glioblastoma Models. Cancers 2019, 11, 359.

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