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

Article

Send article

Pharmacological WNT inhibition acts synergistically with chemo- and radiotherapy in glioblastoma through aldehyde dehydrogenase 3A1

Meeting Abstract

Search Medline for

  • Abigail Suwala - Department of Neurosurgery, University Medical Center, Düsseldorf, Deutschland
  • Katharina Koch - Department of Neurosurgery, University Medical Center, Düsseldorf, Deutschland
  • Ulf D. Kahlert - Department of Neurosurgery, University Medical Center, Düsseldorf, Department of Neurosurgery and Pediatric Neurosurgery, Medical University Lublin, Poland, Düsseldorf/Lublin, Deutschland
  • Jarek Maciaczyk - Department of Neurosurgery, University Medical Center, Düsseldorf, Deutschland

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.03.01

doi: 10.3205/17dgnc371, urn:nbn:de:0183-17dgnc3718

Published: June 9, 2017

© 2017 Suwala 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

Text

Objective: Glioma Stem Cells (GSCs) are considered to be responsible for Glioblastoma's (GBM's) dismal prognosis. Wingless (WNT) promotes their radio- and chemoresistance. We were able to show that pharmacological WNT blockade by means of porcupine inhibition with LGK974 acts synergistically with Temozolomide (TMZ) and γ-irradiation in terms of growth in vitro. Downstream global transcriptome profiling and targeted protein analyzes identified ALDH3A1, a protein that catalyzes the oxidation of aldehydes, to be exclusively regulated under combination therapy.

Methods: At first we investigated different cell lines on their MGMT promoter methylation status to define cell lines resistant to the standard chemotherapeutic drug TMZ. For further analyzes we chose two cell lines resistant and sensitive to TMZ, respectively. IC50 concentrations of TMZ and LGK974 as well as IC50 dose concerning irradiation were defined by means of suppressed viability. Effectiveness of different concentration of each single therapy and in combination with LGK974 was determined to create a drug-response-curve for analyzing synergy. Performing an Affymetrix GeneChip gene expression microarray we searched for genes involved in the observed synergistic effect and validated our results on gene and protein expression levels (qPCR/Western Blot) by using knockdowns created by CRISPR/Cas9.

Results: We observed a significant synergy of combining irradiation/TMZ and LGK974 in all cell lines. Microarray analysis revealed ALDH3A1 to be a potential effector of WNT inhibition. Knocking down of ALDH3A1 led to reduced viability in vitro.

Conclusion: Our results confirm the potential benefit of combining TMZ or irradiation with the WNT inhibitor LGK974 to overcome therapy-resistance in GBM, which seems to be independent of base line MGMT activation levels. Furthermore we hypothesize that ALDH3A1 might serve as an efficient therapeutic target to induce sensitivity against TMZ in glioma cells.