title: VB-111: a novel anti-vascular therapeutic for glioblastoma multiforme.
abstract: Glioblastoma multiforme (GBM) is among the most highly vascularized of solid tumors, contributing to the infiltrative nature of the disease, and conferring poor outcome. Due to the critical dependency of GBM on growth of new endothelial vasculature, we evaluated the preclinical activity of a novel adenoviral gene therapy that targets the endothelium within newly formed blood vessels for apoptosis. VB-111, currently in phase II clinical trials, consists of a non-replicating Adenovirus 5 (El deleted) carrying a proapoptotic human Fas-chimera (transgene) under the control of a modified murine promoter (PPE-1-3×) which specifically targets endothelial cells within the tumor vasculature. Here we report that a single intravenous dose of 2.5 × 10(11) or 1 × 10(11) VPs was sufficient to extend survival in nude rats bearing U87MG-luc2 or nude mice bearing U251-luc, respectively. Bioluminescence imaging of nude rats showed that VB-111 effectively inhibited tumor growth within four weeks of treatment. This was confirmed in a select group of animals by MRI. In our mouse model we observed that 3 of 10 nude mice treated with VB-111 completely lost U251 luciferase signal and were considered long term survivors. To assess the antiangiogenic effects of VB-111, we evaluated the tumor-associated microvaculature by CD31, a common marker of neovascularization, and found a significant decrease in the microvessel density by IHC. We further assessed the neovasculature by confocal microscopy and found that VB-111 inhibits vascular density in two separate mouse models bearing U251-RFP xenografts. Collectively, this study supports the clinical development of VB-111 as a treatment for GBM.
authors.affiliation: Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Gruslova
authors.affiliation: Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Cavazos
authors.affiliation: Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Miller
authors.affiliation: VBL Therapeutics, 6 Jonathan Netanyahu St., Or Yehuda, 60376, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Breitbart
authors.affiliation: VBL Therapeutics, 6 Jonathan Netanyahu St., Or Yehuda, 60376, Israel.
authors.forename: Yael C
authors.initials: YC
authors.lastname: Cohen
authors.affiliation: VBL Therapeutics, 6 Jonathan Netanyahu St., Or Yehuda, 60376, Israel.
authors.forename: Livnat
authors.initials: L
authors.lastname: Bangio
authors.affiliation: VBL Therapeutics, 6 Jonathan Netanyahu St., Or Yehuda, 60376, Israel.
authors.forename: Niva
authors.initials: N
authors.lastname: Yakov
authors.affiliation: Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA.
authors.forename: Anu
authors.initials: A
authors.lastname: Soundararajan
authors.affiliation: Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Floyd
authors.affiliation: Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA. brennera@uthscsa.edu.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brenner
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D043925:Angiogenesis Inducing Agents / Q000627:therapeutic use*; D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods; D005909:Glioblastoma / Q000628:therapy*; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000628:therapy*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D018709:Statistics, Nonparametric; D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000235:genetics
chemical_list: D043925:Angiogenesis Inducing Agents; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor
keywords: Angiogenesis; Gene therapy; Glioblastoma; Tumor vasculature; VB-111