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71. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
9. Joint Meeting mit der Japanischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

21.06. - 24.06.2020

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An in vitro technology to score therapeutic efficacy and risk-potential of substances for targeting brain tumours

Eine in vitro Technologie zur Abschätzung der Effektivität und des Risikopotentials von Substanzen zur Behandlung von Hirntumoren

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  • Katharina Koch - Heinrich-Heine-Universität Düsseldorf, Neurochirurgie, Düsseldorf, Deutschland
  • Rudolf Hartmann - Forschungszentrum Jülich, Institute for Complex Systems (ICS-6), Structural Biochemistry and JuStruct, Jülich, Deutschland
  • Nerantzoula Tsiampali - Heinrich-Heine-Universität Düsseldorf, Neurochirurgie, Düsseldorf, Deutschland
  • Constanze Uhlmann - Heinrich-Heine-Universität Düsseldorf, Neurochirurgie, Düsseldorf, Deutschland
  • Xiaoling He - University of Cambridge, Clinical Neurosciences, Cambridge, United Kingdom
  • Marcel Alexander Kamp - Heinrich-Heine-Universität Düsseldorf, Neurochirurgie, Düsseldorf, Deutschland
  • Michael Sabel - Heinrich-Heine-Universität Düsseldorf, Neurochirurgie, Düsseldorf, Deutschland
  • Roger Barker - University of Cambridge, Clinical Neurosciences, Cambridge, United Kingdom
  • Dieter Willbold - Forschungszentrum Jülich, Institute for Complex Systems (ICS-6), Structural Biochemistry and JuStruct, Jülich, Deutschland; Heinrich-Heine-Universität Düsseldorf, Physikalische Biologie, Düsseldorf, Deutschland
  • Hans-Jakob Steiger - Heinrich-Heine-Universität Düsseldorf, Neurochirurgie, Düsseldorf, Deutschland
  • Jaroslaw Maciaczyk - Heinrich-Heine-Universität Düsseldorf, Neurochirurgie, Düsseldorf, Deutschland; University of Otago, Surgical Sciences, Dunedin, New Zealand
  • presenting/speaker Ulf Dietrich Kahlert - Heinrich-Heine-Universität Düsseldorf, Neurochirurgie, Düsseldorf, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 71. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 9. Joint Meeting mit der Japanischen Gesellschaft für Neurochirurgie. sine loco [digital], 21.-24.06.2020. Düsseldorf: German Medical Science GMS Publishing House; 2020. DocP188

doi: 10.3205/20dgnc473, urn:nbn:de:0183-20dgnc4734

Published: June 26, 2020

© 2020 Koch 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: The upregulation of anabolic processes to maintain high rates of cellular turnover is considered the cancers Achilles’ heel. The intervention in altered metabolic pathways of cancer cells have emerged as a promising strategy to develop new treatments and diagnostic procedures. Thereby, the development of pharmacological inhibitors of metabolic enzymes plays a central role due to its effectiveness in targeting cancer cells. Nevertheless, severe adverse effects hinder the efficient clinical translation of promising metabolic enzyme inhibitors and causes a burden on patients and funding bodies. Improved early stage risk-assessment to characterize the specificity of test substances is therefore highly warranted. Here we present a metabologenomic in vitro tool to assess therapeutic efficacy and perform risk assessment of pharmacological glutaminase (GLS) inhibitors in the context of neuro-oncology.

Methods: A panel of glioblastoma stem-like cell models grown as neurospheres (GSCs) are treated with inhibitors of GLS. Mode of action was characterized by performing various functional in vitro assays such as quantification of cellular growth, clonogenicity, and analysis of cell cycle. Moreover, quantification of the abundance of intracellular metabolites in GSCs subjected to substance treatment, was used to estimate the efficacy of the GLS inhibitor.

Results: Treatment with small molecule inhibitors compound 968 and CB839 effectively diminished cell growth and in vitro clonogenicity of glioblastoma 3D cultures. However, metabolic monitoring revealed that only CB839 inhibited GLS enzymatic activity thereby limiting the influx of glutamine derivates into the TCA cycle. Nevertheless, the effects of both inhibitors were highly GLS specific, since treatment sensitivity markedly correlated with GLS protein expression. Strikingly, we found GLS overexpressed in in vitro GSC models as compared to non-cancerous neural stem cells (NSC).

Conclusion: Pharmacologic GLS inhibition is a promising strategy to eradicate GSCs. The incorporation of a multi-parameter mode of action analysis as well as the inclusion of in vitro control systems into early stage substance testing is helpful in identifying test compounds with elevated off-target risk. The application of metabologenomics may be helpful in early stage drug development to evaluate toxicity or precision medicine.