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73. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Griechischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

29.05. - 01.06.2022, Köln

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A target therapy approach for BRAF mutant Glioblastoma with human preclinical glioblastoma model

Ein zielgerichteter Therapieansatz für das BRAF-mutierte Glioblastom mit einem humanen präklinischen Glioblastom-Modell

Meeting Abstract

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  • presenting/speaker Junyi Zhang - Universitätsklinikum Freiburg, Freiburg i. Br., Deutschland
  • presenting/speaker Vidhya Madapusi Ravi - Universitätsklinikum Freiburg, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Translational NeuroOncology Research Group, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Neuroelectronic Systems, Freiburg i. Br., Deutschland
  • Kevin Joseph - Universitätsklinikum Freiburg, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Translational NeuroOncology Research Group, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg i. Br., Deutschland
  • Jürgen Beck - Universitätsklinikum Freiburg, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Translational NeuroOncology Research Group, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg i. Br., Deutschland
  • Oliver Schnell - Universitätsklinikum Freiburg, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Translational NeuroOncology Research Group, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg i. Br., Deutschland
  • Dieter Henrik Heiland - Universitätsklinikum Freiburg, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Translational NeuroOncology Research Group, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg i. Br., Deutschland

Deutsche Gesellschaft für Neurochirurgie. 73. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Griechischen Gesellschaft für Neurochirurgie. Köln, 29.05.-01.06.2022. Düsseldorf: German Medical Science GMS Publishing House; 2022. DocP058

doi: 10.3205/22dgnc369, urn:nbn:de:0183-22dgnc3690

Published: May 25, 2022

© 2022 Zhang 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: Glioblastoma (GBM) is the most common primary malignant tumor in central nervous system, with median post-diagnosis survival of <15 months. The incredible heterogeneity exhibited by GBM highlights its incurable nature. Referring to specific mutations of the GBM, 40% of GBM’s harbor EGFR alterations, whereas BRAF alterations are rare (1-2%). The BRAF mutation is reported to regulate cell proliferation and apoptosis based on the BRAF/MEKpathway. Since, the mechanisms within BRAF mutated GBM remain unclear, here we present a novel personalized human GBM model of evaluate the efficacy of various BRAF target therapies.

Methods: Discarded non-neoplastic cortical tissue from a BRAF - GBM was sectioned and inoculated with patient self-derived BRAF+ GBM cells, establishing an ex vivo human BRAF+ GBM model. Tumor growth was live tracked over the culture period (10days), with and without clinically approved BRAF and MEK inhibitors and vitality of the sections was quantified using imaging modalities.

Results: Tumor growth quantification revealed a significant reduction (p=0.001) of tumor volume upon combined treatment with a MEK inhibitor (Trametinib, 5nM) and a new generation BRAF inhibitor (Vemurafenib, 10nM) compared to a standard treatment of MEK inhibitor (Trametinib, 5nM) and an old generation BRAF inhibitor (Dabrafenib, 10nM). Immunohistochemistry based quantification also revealed no toxic effect of the drug on the microenvironment validated using NeuN (for Neurons) and GFAP/IBA (for glial cells) antibodies. Further, there is a significant reduction (p=0.005) of pERK and pAKT expression on the sections with the combination therapies (Trametinib+ Vemurafenib) compared to monotherapies and standard combinations.

Conclusion: Our findings show that targeted therapy could be beneficial for patients with glioblastoma harboring BRAF mutation, and establishment of human based personalized model would be useful to investigate the influence of different chemotherapies on the immunosuppressive tumor microenvironment.