gms | German Medical Science

68th Annual Meeting of the German Society of Neurosurgery (DGNC)
7th Joint Meeting with the British Neurosurgical Society (SBNS)

German Society of Neurosurgery (DGNC)

14 - 17 May 2017, Magdeburg

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Combined inhibition of mitochondrial matrix chaperones and Bcl-xL yields synthetic lethality in glioma

Meeting Abstract

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  • Georg Karpel-Massler - Neurochirurgische Klinik der Universität Ulm, Ulm, Deutschland
  • Chang Shu - Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, United States
  • Jeffrey Bruce - Depertment of Neurosurgery, Columbia University Medical Center, New York, NY, United States
  • Peter Canoll - Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, United States
  • Dario Altieri - Wistar Institute, Philadelphia, PA, United States
  • Markus Siegelin - Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, United States

Deutsche Gesellschaft für Neurochirurgie. Society of British Neurological Surgeons. 68. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 7. Joint Meeting mit der Society of British Neurological Surgeons (SBNS). Magdeburg, 14.-17.05.2017. Düsseldorf: German Medical Science GMS Publishing House; 2017. DocMi.04.03

doi: 10.3205/17dgnc381, urn:nbn:de:0183-17dgnc3818

Published: June 9, 2017

© 2017 Karpel-Massler et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.

Outline

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Objective: We show that combined targeting of the mitochondrial Hsp90 chaperone network and inhibition of the anti-apoptotic Bcl-2 family member Bcl-xL induces synthetic lethality in human gliomas.

Methods: The biological and molecular effects of a combined treatment with the Bcl-xL inhibitor ABT263 and the mitochondrial Hsp90 chaperone inhibitor Gamitrinib-TPP were examined in different pre-clinical glioma models including primary cultures, glioma stem-like cells in vitro and multiple human patient-derived orthotopic glioblastoma xenografts (PDX) in vivo.

Results: Combined treatment with ABT263 and Gamitrinib-TPP yields a synergistic anti-proliferative and pro-apoptotic activity. On the molecular level, this response is mediated by a strong induction of endoplasmic reticulum-stress which was characterized by an increased activation of activating transcription factor 4 through a PERK-dependent mechanism and subsequent up-regulation of pro-apoptotic Noxa. In vivo, the combination therapy lead to a significant prolongation of survival in two orthotopic patient-derived xenograft models of glioblastoma.

Conclusion: Combined inhibition of mitochondrial matrix chaperones and Bcl-xL represents a promising new therapeutic strategy for the treatment of gliomas.