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Adjuvant therapeutic potential of tonabersat in the standard treatment of glioblastoma : a preclinical F98 glioblastoma rat model study

Valerie De Meulenaere (UGent) , Ellen Bonte, Jeroen Verhoeven (UGent) , Jean-Pierre Kalala Okito (UGent) , Leen Pieters (UGent) , Anne Vral (UGent) , Olivier De Wever (UGent) , Luc Leybaert (UGent) , Ingeborg Goethals (UGent) , Christian Vanhove (UGent) , et al.
(2019) PLOS ONE. 14(10).
Author
Organization
Abstract
Purpose Even with an optimal treatment protocol, the median survival of glioblastoma (GB) patients is only 12-15 months. Hence, there is need for novel effective therapies that improve survival outcomes. Recent evidence suggests an important role for connexin (Cx) proteins (especially Cx43) in the microenvironment of malignant glioma. Cx43-mediated gap junctional communication has been observed between tumor cells, between astrocytes and between tumor cells and astrocytes. Therefore, gap junction directed therapy using a pharmacological suppressor or modulator, such as tonabersat, could be a promising target in the treatment of GB. In this preclinical study, we evaluated the possible therapeutic potential of tonabersat in the F98 model. Procedures Female Fischer rats were inoculated with +/- 25.000 F98 tumor cells in the right frontal lobe. Eight days post-inoculation contrast-enhanced T1-weighted (CE-T1w) magnetic resonance (MR) images were acquired to confirm tumor growth in the brain. After tumor confirmation, rats were randomized into a Control Group, a Connexin Modulation Group (CM), a Standard Medical Treatment Group (ST), and a Standard Medical Treatment with adjuvant Connexin Modulation Group (STCM). To evaluate therapy response, T2-weighted (T2w) and CE-T1w sequences were acquired at several time points. Tumor volume analysis was performed on CE-T1w images and statistical analysis was performed using a linear mixed model. Results Significant differences in estimated geometric mean tumor volumes were found between the ST Group and the Control Group and also between the STCM Group and the Control Group. In addition, significant differences in estimated geometric mean tumor volumes between the ST Group and the STCM Group were demonstrated. No significant differences in estimated geometric mean tumor volumes were found between the Control Group and the CM Group. Conclusion Our results demonstrate a therapeutic potential of tonabersat for the treatment of GB when used in combination with radiotherapy and temozolomide chemotherapy.
Keywords
BLOOD-BRAIN-BARRIER, TEMOZOLOMIDE RESISTANCE, GAP-JUNCTIONS, CELLS, TUMORS, CLASSIFICATION, CHEMOTHERAPY, RADIOTHERAPY, CONNEXIN43

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MLA
De Meulenaere, Valerie, et al. “Adjuvant Therapeutic Potential of Tonabersat in the Standard Treatment of Glioblastoma : A Preclinical F98 Glioblastoma Rat Model Study.” PLOS ONE, vol. 14, no. 10, 2019, doi:10.1371/journal.pone.0224130.
APA
De Meulenaere, V., Bonte, E., Verhoeven, J., Kalala Okito, J.-P., Pieters, L., Vral, A., … Deblaere, K. (2019). Adjuvant therapeutic potential of tonabersat in the standard treatment of glioblastoma : a preclinical F98 glioblastoma rat model study. PLOS ONE, 14(10). https://doi.org/10.1371/journal.pone.0224130
Chicago author-date
De Meulenaere, Valerie, Ellen Bonte, Jeroen Verhoeven, Jean-Pierre Kalala Okito, Leen Pieters, Anne Vral, Olivier De Wever, et al. 2019. “Adjuvant Therapeutic Potential of Tonabersat in the Standard Treatment of Glioblastoma : A Preclinical F98 Glioblastoma Rat Model Study.” PLOS ONE 14 (10). https://doi.org/10.1371/journal.pone.0224130.
Chicago author-date (all authors)
De Meulenaere, Valerie, Ellen Bonte, Jeroen Verhoeven, Jean-Pierre Kalala Okito, Leen Pieters, Anne Vral, Olivier De Wever, Luc Leybaert, Ingeborg Goethals, Christian Vanhove, Benedicte Descamps, and Karel Deblaere. 2019. “Adjuvant Therapeutic Potential of Tonabersat in the Standard Treatment of Glioblastoma : A Preclinical F98 Glioblastoma Rat Model Study.” PLOS ONE 14 (10). doi:10.1371/journal.pone.0224130.
Vancouver
1.
De Meulenaere V, Bonte E, Verhoeven J, Kalala Okito J-P, Pieters L, Vral A, et al. Adjuvant therapeutic potential of tonabersat in the standard treatment of glioblastoma : a preclinical F98 glioblastoma rat model study. PLOS ONE. 2019;14(10).
IEEE
[1]
V. De Meulenaere et al., “Adjuvant therapeutic potential of tonabersat in the standard treatment of glioblastoma : a preclinical F98 glioblastoma rat model study,” PLOS ONE, vol. 14, no. 10, 2019.
@article{8633466,
  abstract     = {Purpose
Even with an optimal treatment protocol, the median survival of glioblastoma (GB) patients is only 12-15 months. Hence, there is need for novel effective therapies that improve survival outcomes. Recent evidence suggests an important role for connexin (Cx) proteins (especially Cx43) in the microenvironment of malignant glioma. Cx43-mediated gap junctional communication has been observed between tumor cells, between astrocytes and between tumor cells and astrocytes. Therefore, gap junction directed therapy using a pharmacological suppressor or modulator, such as tonabersat, could be a promising target in the treatment of GB. In this preclinical study, we evaluated the possible therapeutic potential of tonabersat in the F98 model.
Procedures
Female Fischer rats were inoculated with +/- 25.000 F98 tumor cells in the right frontal lobe. Eight days post-inoculation contrast-enhanced T1-weighted (CE-T1w) magnetic resonance (MR) images were acquired to confirm tumor growth in the brain. After tumor confirmation, rats were randomized into a Control Group, a Connexin Modulation Group (CM), a Standard Medical Treatment Group (ST), and a Standard Medical Treatment with adjuvant Connexin Modulation Group (STCM). To evaluate therapy response, T2-weighted (T2w) and CE-T1w sequences were acquired at several time points. Tumor volume analysis was performed on CE-T1w images and statistical analysis was performed using a linear mixed model.
Results
Significant differences in estimated geometric mean tumor volumes were found between the ST Group and the Control Group and also between the STCM Group and the Control Group. In addition, significant differences in estimated geometric mean tumor volumes between the ST Group and the STCM Group were demonstrated. No significant differences in estimated geometric mean tumor volumes were found between the Control Group and the CM Group.
Conclusion
Our results demonstrate a therapeutic potential of tonabersat for the treatment of GB when used in combination with radiotherapy and temozolomide chemotherapy.},
  articleno    = {e0224130},
  author       = {De Meulenaere, Valerie and Bonte, Ellen and Verhoeven, Jeroen and Kalala Okito, Jean-Pierre and Pieters, Leen and Vral, Anne and De Wever, Olivier and Leybaert, Luc and Goethals, Ingeborg and Vanhove, Christian and Descamps, Benedicte and Deblaere, Karel},
  issn         = {1932-6203},
  journal      = {PLOS ONE},
  keywords     = {BLOOD-BRAIN-BARRIER,TEMOZOLOMIDE RESISTANCE,GAP-JUNCTIONS,CELLS,TUMORS,CLASSIFICATION,CHEMOTHERAPY,RADIOTHERAPY,CONNEXIN43},
  language     = {eng},
  number       = {10},
  pages        = {17},
  title        = {Adjuvant therapeutic potential of tonabersat in the standard treatment of glioblastoma : a preclinical F98 glioblastoma rat model study},
  url          = {http://dx.doi.org/10.1371/journal.pone.0224130},
  volume       = {14},
  year         = {2019},
}

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