2. Academic Validation
  3. Intracranial AAV-sTRAIL combined with lanatoside C prolongs survival in an orthotopic xenograft mouse model of invasive glioblastoma

Intracranial AAV-sTRAIL combined with lanatoside C prolongs survival in an orthotopic xenograft mouse model of invasive glioblastoma

  • Mol Oncol. 2016 Apr;10(4):625-34. doi: 10.1016/j.molonc.2015.11.011.
Matheus H W Crommentuijn 1,  Casey A Maguire 2,  Johanna M Niers 1,  W Peter Vandertop 3,  Christian E Badr 2,  Thomas Würdinger 4,  Bakhos A Tannous 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Neuro-oncology Research Group, Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.
  • 4 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.
  • 5 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.
PMID: 26708508 DOI: 10.1016/j.molonc.2015.11.011
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.

Keywords

Adeno-associated virus; Cardiac glycoside; Gene therapy; Glioblastoma; Lanatoside C; TRAIL.

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