Laurèl Rauschenbach1, Anja Wieland2, Roman Reinartz3, Sied Kebir4, Andreas Till3, Marvin Darkwah Oppong5, Celia Dobersalske6, Vivien Ullrich7, Ashar Ahmad8, Ramazan Jabbarli5, Daniela Pierscianek5, Holger Fröhlich9, Matthias Simon10, Oliver Brüstle3, Ulrich Sure5, Martin Glas4, Björn Scheffler11. 1. Institute of Reconstructive Neurobiology, Division of Stem Cell Pathologies, Life and Brain Centre, University of Bonn Medical Faculty and University Hospital Bonn, Germany; DKFZ Division Translational Neurooncology at the West German Cancer Center (WTZ), DKTK Partner Site, University Hospital Essen, Germany; Department of Neurosurgery and Spine Surgery, University Hospital Essen, Germany; German Cancer Consortium (DKTK), Germany. Electronic address: laurel.rauschenbach@uk-essen.de. 2. Institute of Reconstructive Neurobiology, Division of Stem Cell Pathologies, Life and Brain Centre, University of Bonn Medical Faculty and University Hospital Bonn, Germany; Department of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Germany. 3. Institute of Reconstructive Neurobiology, Division of Stem Cell Pathologies, Life and Brain Centre, University of Bonn Medical Faculty and University Hospital Bonn, Germany. 4. DKFZ Division Translational Neurooncology at the West German Cancer Center (WTZ), DKTK Partner Site, University Hospital Essen, Germany; German Cancer Consortium (DKTK), Germany; Division of Clinical Neurooncology, Department of Neurology, University Hospital Essen, Germany. 5. Department of Neurosurgery and Spine Surgery, University Hospital Essen, Germany; German Cancer Consortium (DKTK), Germany. 6. DKFZ Division Translational Neurooncology at the West German Cancer Center (WTZ), DKTK Partner Site, University Hospital Essen, Germany; German Cancer Consortium (DKTK), Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. 7. DKFZ Division Translational Neurooncology at the West German Cancer Center (WTZ), DKTK Partner Site, University Hospital Essen, Germany; German Cancer Consortium (DKTK), Germany. 8. Biomedical Data Science, Bonn-Aachen International Center for Information Technology, University of Bonn, Germany. 9. Biomedical Data Science, Bonn-Aachen International Center for Information Technology, University of Bonn, Germany; Business Area Bioinformatics, Fraunhofer SCAI, Sankt Augustin, Germany. 10. Department of Neurosurgery, University Hospital Bonn, Germany; Department of Neurosurgery, Bethel Clinic Bielefeld, Germany. 11. Institute of Reconstructive Neurobiology, Division of Stem Cell Pathologies, Life and Brain Centre, University of Bonn Medical Faculty and University Hospital Bonn, Germany; DKFZ Division Translational Neurooncology at the West German Cancer Center (WTZ), DKTK Partner Site, University Hospital Essen, Germany; German Cancer Consortium (DKTK), Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
Abstract
BACKGROUND: The protease inhibitor ritonavir (RTV) is a clinical-stage inhibitor of the human immunodeficiency virus. In a drug repositioning approach, we here exhibit the additional potential of RTV to augment current treatment of glioblastoma, the most aggressive primary brain tumour of adulthood. METHODS: We explored the antitumour activity of RTV and mechanisms of action in a broad spectrum of short-term expanded clinical cell samples from primary and recurrent glioblastoma and in a cohort of conventional cell lines and non-tumour human neural controls in vitro. To validate RTV efficacy in monotherapeutic and in combinatorial settings, we used patient-derived xenograft models in a series of in vivo studies. RESULTS: RTV monotherapy induced a selective antineoplastic response and demonstrated cytostatic and anti-migratory activity at clinical plasma peak levels. Additional exposure to temozolomide or irradiation further enhanced the effects synergistically, fostered by mechanisms of autophagy and increased endoplasmic reticulum stress. In xenograft models, we consequently observed increasing overall survival under the combinatorial effect of RTV and temozolomide. CONCLUSIONS: Our data establish RTV as a valuable repositioning candidate for further exploration as an adjunct therapeutic in the clinical care of glioblastoma.
BACKGROUND: The protease inhibitor ritonavir (RTV) is a clinical-stage inhibitor of the human immunodeficiency virus. In a drug repositioning approach, we here exhibit the additional potential of RTV to augment current treatment of glioblastoma, the most aggressive primary brain tumour of adulthood. METHODS: We explored the antitumour activity of RTV and mechanisms of action in a broad spectrum of short-term expanded clinical cell samples from primary and recurrent glioblastoma and in a cohort of conventional cell lines and non-tumourhuman neural controls in vitro. To validate RTV efficacy in monotherapeutic and in combinatorial settings, we used patient-derived xenograft models in a series of in vivo studies. RESULTS:RTV monotherapy induced a selective antineoplastic response and demonstrated cytostatic and anti-migratory activity at clinical plasma peak levels. Additional exposure to temozolomide or irradiation further enhanced the effects synergistically, fostered by mechanisms of autophagy and increased endoplasmic reticulum stress. In xenograft models, we consequently observed increasing overall survival under the combinatorial effect of RTV and temozolomide. CONCLUSIONS: Our data establish RTV as a valuable repositioning candidate for further exploration as an adjunct therapeutic in the clinical care of glioblastoma.
Authors: Marc-Eric Halatsch; Richard E Kast; Georg Karpel-Massler; Benjamin Mayer; Oliver Zolk; Bernd Schmitz; Angelika Scheuerle; Ludwig Maier; Lars Bullinger; Regine Mayer-Steinacker; Carl Schmidt; Katharina Zeiler; Ziad Elshaer; Patricia Panther; Birgit Schmelzle; Anke Hallmen; Annika Dwucet; Markus D Siegelin; Mike-Andrew Westhoff; Kristine Beckers; Gauthier Bouche; Tim Heiland Journal: Neurooncol Adv Date: 2021-06-24