Abstract

The intermediate-conductance calcium-activated potassium channel KCa3.1 has been proposed to be a new potential target for glioblastoma treatment. This study analyzed the effect of combined irradiation and KCa3.1-targeting with TRAM-34 in the syngeneic, immune-competent orthotopic SMA-560/VM/Dk glioma mouse model. Whereas neither irradiation nor TRAM-34 treatment alone meaningfully prolonged the survival of the animals, the combination significantly prolonged the survival of the mice. We found an irradiation-induced hyperinvasion of glioma cells into the brain, which was inhibited by concomitant TRAM-34 treatment. Interestingly, TRAM-34 did neither radiosensitize nor impair SMA-560’s intrinsic migratory capacities in vitro. Exploratory findings hint at increased TGF-β1 signaling after irradiation. On top, we found a marginal upregulation of MMP9 mRNA, which was inhibited by TRAM-34. Last, infiltration of CD3+, CD8+ or FoxP3+ T cells was not impacted by either irradiation or KCa3.1 targeting and we found no evidence of adverse events of the combined treatment. We conclude that concomitant irradiation and TRAM-34 treatment is efficacious in this preclinical glioma model.

Details

Title
Efficacy of combined tumor irradiation and KCa3.1-targeting with TRAM-34 in a syngeneic glioma mouse model
Author
Stransky, Nicolai 1   VIAFID ORCID Logo  ; Ganser, Katrin 2   VIAFID ORCID Logo  ; Quintanilla-Martinez, Leticia 3 ; Gonzalez-Menendez, Irene 3 ; Naumann, Ulrike 4 ; Eckert, Franziska 5   VIAFID ORCID Logo  ; Koch, Pierre 6 ; Huber, Stephan M. 2   VIAFID ORCID Logo  ; Ruth, Peter 7 

1  University of Tübingen, Department of Radiation Oncology, Tübingen, Germany (GRID:grid.10392.39) (ISNI:0000 0001 2190 1447); University of Tübingen, Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, Tübingen, Germany (GRID:grid.10392.39) (ISNI:0000 0001 2190 1447) 
2  University of Tübingen, Department of Radiation Oncology, Tübingen, Germany (GRID:grid.10392.39) (ISNI:0000 0001 2190 1447) 
3  Eberhard Karls University of Tübingen, Institute of Pathology and Neuropathology, Comprehensive Cancer Center, Tübingen, Germany (GRID:grid.10392.39) (ISNI:0000 0001 2190 1447); Eberhard Karls University, Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, Tübingen, Germany (GRID:grid.10392.39) (ISNI:0000 0001 2190 1447) 
4  University of Tübingen, Molecular Neurooncology, Hertie Institute for Clinical Brain Research and Center Neurology, Tübingen, Germany (GRID:grid.10392.39) (ISNI:0000 0001 2190 1447); Gene and RNA Therapy Center (GRTC), Faculty of Medicine University, Tübingen, Germany (GRID:grid.10392.39) 
5  University of Tübingen, Department of Radiation Oncology, Tübingen, Germany (GRID:grid.10392.39) (ISNI:0000 0001 2190 1447); Medical University Vienna, AKH, Department of Radiation Oncology, Comprehensive Cancer Center, Wien, Austria (GRID:grid.22937.3d) (ISNI:0000 0000 9259 8492) 
6  University of Regensburg, Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, Regensburg, Germany (GRID:grid.7727.5) (ISNI:0000 0001 2190 5763) 
7  University of Tübingen, Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, Tübingen, Germany (GRID:grid.10392.39) (ISNI:0000 0001 2190 1447) 
Pages
20604
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-023-47552-4
ProQuest document ID
2892810187
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.