gms | German Medical Science

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

A robot-technology for the acquisition of large-scale in vitro pharmacology-response of brain cancer

Der Einsatz von Roboter-Technologie zur Bestimmung der in vitro Antwort von Hirntumoren auf Substanzapplikation

Meeting Abstract

  • presenting/speaker Andres Vargas-Toscano - Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Deutschland
  • Ann-Christin Nickel - Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Deutschland
  • Michael Hewera - Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Deutschland
  • Marcel Alexander Kamp - Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Deutschland
  • Igor Fischer - Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Deutschland
  • Hans-Jakob Steiger - Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Deutschland
  • Daniel Hänggi - Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Deutschland
  • Ulf Dietrich Kahlert - Heinrich-Heine-Universität Düsseldorf, 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. DocP078

doi: 10.3205/20dgnc365, urn:nbn:de:0183-20dgnc3650

Published: June 26, 2020

© 2020 Vargas-Toscano 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: In vitro pharmacology testing is an assay in early stage in drug development and fundament of various in vitro-diagnostic technologies. Liquid handling systems allow large-scale and highly reproducible allocation of solved components and is a standard assay in industry and routine diagnostics. We implement this technology for the identification of chemo resistance therapies of in vitro processed tumor samples focusing on a stem cell model of glioblastoma. Stem-like cells in cancer are involved in tumor progression and mediating resistance to therapy.

Methods: A drug library composing 167 FDA-approved, molecularly diverse compounds with reported brain tissue penetration capacity was assembled. A pipetting scheme was developed and programmed to instruct a BiomekFXProbotic workstation perform a high resolution (≥ 5 concentrations/substance) drug response testing. Cellular growth was used as reporter assay. The GSC model was expanded under neurosphere conditions. Statistical significant responses result in ranking the test substances according to therapeutic potential using IC50 values.

Results: Repetitive drug-dose repose profiles were generated. Out of the tested compounds, 22 exhibited a homogeneous decrease on cellular growth in the nm concentration range compared to the vehicle treatment control (P<0,001) indicating physiological meaningfulness therapeutic potential against this tumor model. Twelve of which had intermediate potency (between 50-25% viability decrease) and 10 showed high potency (>75% viability decrease). These compounds include prominent mTOR-pathway inhibitor Everolimus or cytostatics Doxorubicin but also identified novel repurposed compounds such as Trihexyphenidyl (muscarinic receptor antagonist used in symptomatic treatment of Parkinson), Clonidine (anti-hypertensive) and Rizatriptan (anti-migraine).

Conclusion: We established an automated test platform for reproducible medium-throughput in vitro pharmacology which could be useful in personalized medicine of neuro oncology. Mode of Action: characterization and validation of therapeutic meaningfulness of the in vitro results by in vivo trial are underway. Given the assembly of FDA approved drugs this efforts support clinical translation. Moreover, applying cell models equipped with reporter constructs, this screening tool is suitable to identify pharmacological modulators of transcriptional activity.