Inhibition of PlexA1-mediated brain tumor growth and tumor-associated angiogenesis using a transmembrane domain targeting peptide

// Laurent Jacob 1, 2, 3, 4 , Paul Sawma 5, * , Norbert Garnier 6, * , Lionel A.T. Meyer 1, 2, 3, 4, * , Justine Fritz 1, 2, 3, 4, * , Thomas Hussenet 1, 2, 3, 4, * , Caroline Spenlé 1, 2, 3, 4, * , Jacky Goetz 1, 2, 3, 4, 7 , Julien Vermot 7 , Aurore Fernandez 1, 2, 3, 4 , Nadège Baumlin 1, 2, 3, 4 , Samia Aci-Sèche 6, 8 , Gertraud Orend 1, 2, 3, 4 , Guy Roussel 1, 2, 3, 4 , Gérard Crémel 1, 2, 3, 4 , Monique Genest 6 , Pierre Hubert 5 , Dominique Bagnard 1, 2, 3, 4 1 MN3T Team, INSERM U1109, Strasbourg, France 2 Université de Strasbourg, Strasbourg, France 3 LabEx Medalis, Université de Strasbourg, Strasbourg, France 4 Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France 5 Laboratoire d’Ingénierie des Systèmes Macromoléculaires (LISM), UMR 7255, CNRS-Aix Marseille Université, Marseille, France 6 Centre de Biophysique Moléculaire, UPR 4301, CNRS, Affiliated to the University of Orléans, Orléans, France 7 Institute of Genetics and Molecular and Cellular Biology (IGBMC), CNRS/INSERM/UDS, Illkirch, France 8 Current address: Institut de Chimie Organique et Analytique UMR, Université d'Orléans, Orléans, France * These authors contributed equally to this work Correspondence to: Dominique Bagnard, email: bagnard@unistra.fr Keywords: plexin, anti-cancer drug, angiogenesis, biomarker, glioblastoma Received: July 11, 2016      Accepted: July 21, 2016      Published: August 05, 2016 ABSTRACT The neuropilin-plexin receptor complex regulates tumor cell migration and proliferation and thus is an interesting therapeutic target. High expression of neuropilin-1 is indeed associated with a bad prognosis in glioma patients. Q-RTPCR and tissue-array analyses showed here that Plexin-A1 is highly expressed in glioblastoma and that the highest level of expression correlates with the worse survival of patients. We next identified a developmental and tumor-associated pro-angiogenic role of Plexin-A1. Hence, by using molecular simulations and a two-hybrid like assay in parallel with biochemical and cellular assays we developed a specific Plexin-A1 peptidic antagonist disrupting transmembrane domain-mediated oligomerization of the receptor and subsequent signaling and functional activity. We found that this peptide exhibits anti-tumor activity in vivo on different human glioblastoma models including glioma cancer stem cells. Thus, screening Plexin-A1 expression and targeting Plexin-A1 in glioblastoma patients exhibit diagnostic and therapeutic value.