title: Intracranial AAV-sTRAIL combined with lanatoside C prolongs survival in an orthotopic xenograft mouse model of invasive glioblastoma.
abstract: Glioblastoma (GBM) is the most common malignant brain tumor in adults. We designed an adeno-associated virus (AAV) vector for intracranial delivery of secreted, soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) to GBM tumors in mice and combined it with the TRAIL-sensitizing cardiac glycoside, lanatoside C (lan C). We applied this combined therapy to two different GBM models using human U87 glioma cells and primary patient-derived GBM neural spheres in culture and in orthotopic GBM xenograft models in mice. In U87 cells, conditioned medium from AAV2-sTRAIL expressing cells combined with lan C induced 80% cell death. Similarly, lan C sensitized primary GBM spheres to sTRAIL causing over 90% cell death. In mice bearing intracranial U87 tumors treated with AAVrh.8-sTRAIL, administration of lan C caused a decrease in tumor-associated Fluc signal, while tumor size increased within days of stopping the treatment. Another round of lan C treatment re-sensitized GBM tumor to sTRAIL-induced cell death. AAVrh.8-sTRAIL treatment alone and combined with lanatoside C resulted in a significant decrease in tumor growth and longer survival of mice bearing orthotopic invasive GBM brain tumors. In summary, AAV-sTRAIL combined with lanatoside C induced cell death in U87 glioma cells and patient-derived GBM neural spheres in culture and in vivo leading to an increased in overall mice survival.
authors.affiliation: Experimental Therapeutics and Molecular Imaging Laboratory, Neuroscience Center, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Program in Neuroscience, Harvard Medical School, Boston, MA, USA; Neuro-oncology Research Group, Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Matheus H W
authors.initials: MH
authors.lastname: Crommentuijn
authors.affiliation: Experimental Therapeutics and Molecular Imaging Laboratory, Neuroscience Center, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Program in Neuroscience, Harvard Medical School, Boston, MA, USA.
authors.forename: Casey A
authors.initials: CA
authors.lastname: Maguire
authors.affiliation: Experimental Therapeutics and Molecular Imaging Laboratory, Neuroscience Center, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Program in Neuroscience, Harvard Medical School, Boston, MA, USA; Neuro-oncology Research Group, Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Niers
authors.affiliation: Neuro-oncology Research Group, Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: W Peter
authors.initials: WP
authors.lastname: Vandertop
authors.affiliation: Experimental Therapeutics and Molecular Imaging Laboratory, Neuroscience Center, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Program in Neuroscience, Harvard Medical School, Boston, MA, USA.
authors.forename: Christian E
authors.initials: CE
authors.lastname: Badr
authors.affiliation: Program in Neuroscience, Harvard Medical School, Boston, MA, USA; Neuro-oncology Research Group, Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Würdinger
authors.affiliation: Experimental Therapeutics and Molecular Imaging Laboratory, Neuroscience Center, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Program in Neuroscience, Harvard Medical School, Boston, MA, USA. Electronic address: btannous@hms.harvard.edu.
authors.forename: Bakhos A
authors.initials: BA
authors.lastname: Tannous
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D000229:Dependovirus; D005822:Genetic Vectors; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D064593:Heterografts; D006801:Humans; D007799:Lanatosides / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D007799:Lanatosides; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C036572:lanatoside A
keywords: Adeno-associated virus; Cardiac glycoside; Gene therapy; Glioblastoma; Lanatoside C; TRAIL