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Monotherapy efficacy of blood–brain barrier permeable small molecule reactivators of protein phosphatase 2A in glioblastoma

Glioblastoma is a fatal disease in which most targeted therapies have clinically failed. However, pharmacological reactivation of tumour suppressors has not been thoroughly studied as yet as a glioblastoma therapeutic strategy. Tumour suppressor protein phosphatase 2A is inhibited by non-genetic mec...

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Autores principales: Merisaari, Joni, Denisova, Oxana V, Doroszko, Milena, Le Joncour, Vadim, Johansson, Patrik, Leenders, William P J, Kastrinsky, David B, Zaware, Nilesh, Narla, Goutham, Laakkonen, Pirjo, Nelander, Sven, Ohlmeyer, Michael, Westermarck, Jukka
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425423/
https://www.ncbi.nlm.nih.gov/pubmed/32954276
http://dx.doi.org/10.1093/braincomms/fcaa002
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author Merisaari, Joni
Denisova, Oxana V
Doroszko, Milena
Le Joncour, Vadim
Johansson, Patrik
Leenders, William P J
Kastrinsky, David B
Zaware, Nilesh
Narla, Goutham
Laakkonen, Pirjo
Nelander, Sven
Ohlmeyer, Michael
Westermarck, Jukka
author_facet Merisaari, Joni
Denisova, Oxana V
Doroszko, Milena
Le Joncour, Vadim
Johansson, Patrik
Leenders, William P J
Kastrinsky, David B
Zaware, Nilesh
Narla, Goutham
Laakkonen, Pirjo
Nelander, Sven
Ohlmeyer, Michael
Westermarck, Jukka
author_sort Merisaari, Joni
collection PubMed
description Glioblastoma is a fatal disease in which most targeted therapies have clinically failed. However, pharmacological reactivation of tumour suppressors has not been thoroughly studied as yet as a glioblastoma therapeutic strategy. Tumour suppressor protein phosphatase 2A is inhibited by non-genetic mechanisms in glioblastoma, and thus, it would be potentially amendable for therapeutic reactivation. Here, we demonstrate that small molecule activators of protein phosphatase 2A, NZ-8-061 and DBK-1154, effectively cross the in vitro model of blood–brain barrier, and in vivo partition to mouse brain tissue after oral dosing. In vitro, small molecule activators of protein phosphatase 2A exhibit robust cell-killing activity against five established glioblastoma cell lines, and nine patient-derived primary glioma cell lines. Collectively, these cell lines have heterogeneous genetic background, kinase inhibitor resistance profile and stemness properties; and they represent different clinical glioblastoma subtypes. Moreover, small molecule activators of protein phosphatase 2A were found to be superior to a range of kinase inhibitors in their capacity to kill patient-derived primary glioma cells. Oral dosing of either of the small molecule activators of protein phosphatase 2A significantly reduced growth of infiltrative intracranial glioblastoma tumours. DBK-1154, with both higher degree of brain/blood distribution, and more potent in vitro activity against all tested glioblastoma cell lines, also significantly increased survival of mice bearing orthotopic glioblastoma xenografts. In summary, this report presents a proof-of-principle data for blood–brain barrier—permeable tumour suppressor reactivation therapy for glioblastoma cells of heterogenous molecular background. These results also provide the first indications that protein phosphatase 2A reactivation might be able to challenge the current paradigm in glioblastoma therapies which has been strongly focused on targeting specific genetically altered cancer drivers with highly specific inhibitors. Based on demonstrated role for protein phosphatase 2A inhibition in glioblastoma cell drug resistance, small molecule activators of protein phosphatase 2A may prove to be beneficial in future glioblastoma combination therapies.
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spelling pubmed-74254232020-09-17 Monotherapy efficacy of blood–brain barrier permeable small molecule reactivators of protein phosphatase 2A in glioblastoma Merisaari, Joni Denisova, Oxana V Doroszko, Milena Le Joncour, Vadim Johansson, Patrik Leenders, William P J Kastrinsky, David B Zaware, Nilesh Narla, Goutham Laakkonen, Pirjo Nelander, Sven Ohlmeyer, Michael Westermarck, Jukka Brain Commun Original Article Glioblastoma is a fatal disease in which most targeted therapies have clinically failed. However, pharmacological reactivation of tumour suppressors has not been thoroughly studied as yet as a glioblastoma therapeutic strategy. Tumour suppressor protein phosphatase 2A is inhibited by non-genetic mechanisms in glioblastoma, and thus, it would be potentially amendable for therapeutic reactivation. Here, we demonstrate that small molecule activators of protein phosphatase 2A, NZ-8-061 and DBK-1154, effectively cross the in vitro model of blood–brain barrier, and in vivo partition to mouse brain tissue after oral dosing. In vitro, small molecule activators of protein phosphatase 2A exhibit robust cell-killing activity against five established glioblastoma cell lines, and nine patient-derived primary glioma cell lines. Collectively, these cell lines have heterogeneous genetic background, kinase inhibitor resistance profile and stemness properties; and they represent different clinical glioblastoma subtypes. Moreover, small molecule activators of protein phosphatase 2A were found to be superior to a range of kinase inhibitors in their capacity to kill patient-derived primary glioma cells. Oral dosing of either of the small molecule activators of protein phosphatase 2A significantly reduced growth of infiltrative intracranial glioblastoma tumours. DBK-1154, with both higher degree of brain/blood distribution, and more potent in vitro activity against all tested glioblastoma cell lines, also significantly increased survival of mice bearing orthotopic glioblastoma xenografts. In summary, this report presents a proof-of-principle data for blood–brain barrier—permeable tumour suppressor reactivation therapy for glioblastoma cells of heterogenous molecular background. These results also provide the first indications that protein phosphatase 2A reactivation might be able to challenge the current paradigm in glioblastoma therapies which has been strongly focused on targeting specific genetically altered cancer drivers with highly specific inhibitors. Based on demonstrated role for protein phosphatase 2A inhibition in glioblastoma cell drug resistance, small molecule activators of protein phosphatase 2A may prove to be beneficial in future glioblastoma combination therapies. Oxford University Press 2020-01-11 /pmc/articles/PMC7425423/ /pubmed/32954276 http://dx.doi.org/10.1093/braincomms/fcaa002 Text en © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Article
Merisaari, Joni
Denisova, Oxana V
Doroszko, Milena
Le Joncour, Vadim
Johansson, Patrik
Leenders, William P J
Kastrinsky, David B
Zaware, Nilesh
Narla, Goutham
Laakkonen, Pirjo
Nelander, Sven
Ohlmeyer, Michael
Westermarck, Jukka
Monotherapy efficacy of blood–brain barrier permeable small molecule reactivators of protein phosphatase 2A in glioblastoma
title Monotherapy efficacy of blood–brain barrier permeable small molecule reactivators of protein phosphatase 2A in glioblastoma
title_full Monotherapy efficacy of blood–brain barrier permeable small molecule reactivators of protein phosphatase 2A in glioblastoma
title_fullStr Monotherapy efficacy of blood–brain barrier permeable small molecule reactivators of protein phosphatase 2A in glioblastoma
title_full_unstemmed Monotherapy efficacy of blood–brain barrier permeable small molecule reactivators of protein phosphatase 2A in glioblastoma
title_short Monotherapy efficacy of blood–brain barrier permeable small molecule reactivators of protein phosphatase 2A in glioblastoma
title_sort monotherapy efficacy of blood–brain barrier permeable small molecule reactivators of protein phosphatase 2a in glioblastoma
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425423/
https://www.ncbi.nlm.nih.gov/pubmed/32954276
http://dx.doi.org/10.1093/braincomms/fcaa002
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