Cytotoxic effects and tolerability of gemcitabine and axitinib in a xenograft model for c-myc amplified medulloblastoma

Abstract Medulloblastoma is the most common high-grade brain tumor in childhood. Medulloblastomas with c-myc amplification, classified as group 3, are the most aggressive among the four disease subtypes resulting in a 5-year overall survival of just above 50%. Despite current intensive therapy regim...

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Autores principales:	Stefanie Schwinn, Zeinab Mokhtari, Sina Thusek, Theresa Schneider, Anna-Leena Sirén, Nicola Tiemeyer, Ignazio Caruana, Evelina Miele, Paul G. Schlegel, Andreas Beilhack, Matthias Wölfl
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d110698f9bd945e084481c034902c1df
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spelling	oai:doaj.org-article:d110698f9bd945e084481c034902c1df2021-12-02T15:22:56ZCytotoxic effects and tolerability of gemcitabine and axitinib in a xenograft model for c-myc amplified medulloblastoma10.1038/s41598-021-93586-x2045-2322https://doaj.org/article/d110698f9bd945e084481c034902c1df2021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93586-xhttps://doaj.org/toc/2045-2322Abstract Medulloblastoma is the most common high-grade brain tumor in childhood. Medulloblastomas with c-myc amplification, classified as group 3, are the most aggressive among the four disease subtypes resulting in a 5-year overall survival of just above 50%. Despite current intensive therapy regimens, patients suffering from group 3 medulloblastoma urgently require new therapeutic options. Using a recently established c-myc amplified human medulloblastoma cell line, we performed an in-vitro-drug screen with single and combinatorial drugs that are either already clinically approved or agents in the advanced stage of clinical development. Candidate drugs were identified in vitro and then evaluated in vivo. Tumor growth was closely monitored by BLI. Vessel development was assessed by 3D light-sheet-fluorescence-microscopy. We identified the combination of gemcitabine and axitinib to be highly cytotoxic, requiring only low picomolar concentrations when used in combination. In the orthotopic model, gemcitabine and axitinib showed efficacy in terms of tumor control and survival. In both models, gemcitabine and axitinib were better tolerated than the standard regimen comprising of cisplatin and etoposide phosphate. 3D light-sheet-fluorescence-microscopy of intact tumors revealed thinning and rarefication of tumor vessels, providing one explanation for reduced tumor growth. Thus, the combination of the two drugs gemcitabine and axitinib has favorable effects on preventing tumor progression in an orthotopic group 3 medulloblastoma xenograft model while exhibiting a favorable toxicity profile. The combination merits further exploration as a new approach to treat high-risk group 3 medulloblastoma.Stefanie SchwinnZeinab MokhtariSina ThusekTheresa SchneiderAnna-Leena SirénNicola TiemeyerIgnazio CaruanaEvelina MielePaul G. SchlegelAndreas BeilhackMatthias WölflNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Stefanie Schwinn Zeinab Mokhtari Sina Thusek Theresa Schneider Anna-Leena Sirén Nicola Tiemeyer Ignazio Caruana Evelina Miele Paul G. Schlegel Andreas Beilhack Matthias Wölfl Cytotoxic effects and tolerability of gemcitabine and axitinib in a xenograft model for c-myc amplified medulloblastoma
description	Abstract Medulloblastoma is the most common high-grade brain tumor in childhood. Medulloblastomas with c-myc amplification, classified as group 3, are the most aggressive among the four disease subtypes resulting in a 5-year overall survival of just above 50%. Despite current intensive therapy regimens, patients suffering from group 3 medulloblastoma urgently require new therapeutic options. Using a recently established c-myc amplified human medulloblastoma cell line, we performed an in-vitro-drug screen with single and combinatorial drugs that are either already clinically approved or agents in the advanced stage of clinical development. Candidate drugs were identified in vitro and then evaluated in vivo. Tumor growth was closely monitored by BLI. Vessel development was assessed by 3D light-sheet-fluorescence-microscopy. We identified the combination of gemcitabine and axitinib to be highly cytotoxic, requiring only low picomolar concentrations when used in combination. In the orthotopic model, gemcitabine and axitinib showed efficacy in terms of tumor control and survival. In both models, gemcitabine and axitinib were better tolerated than the standard regimen comprising of cisplatin and etoposide phosphate. 3D light-sheet-fluorescence-microscopy of intact tumors revealed thinning and rarefication of tumor vessels, providing one explanation for reduced tumor growth. Thus, the combination of the two drugs gemcitabine and axitinib has favorable effects on preventing tumor progression in an orthotopic group 3 medulloblastoma xenograft model while exhibiting a favorable toxicity profile. The combination merits further exploration as a new approach to treat high-risk group 3 medulloblastoma.
format	article
author	Stefanie Schwinn Zeinab Mokhtari Sina Thusek Theresa Schneider Anna-Leena Sirén Nicola Tiemeyer Ignazio Caruana Evelina Miele Paul G. Schlegel Andreas Beilhack Matthias Wölfl
author_facet	Stefanie Schwinn Zeinab Mokhtari Sina Thusek Theresa Schneider Anna-Leena Sirén Nicola Tiemeyer Ignazio Caruana Evelina Miele Paul G. Schlegel Andreas Beilhack Matthias Wölfl
author_sort	Stefanie Schwinn
title	Cytotoxic effects and tolerability of gemcitabine and axitinib in a xenograft model for c-myc amplified medulloblastoma
title_short	Cytotoxic effects and tolerability of gemcitabine and axitinib in a xenograft model for c-myc amplified medulloblastoma
title_full	Cytotoxic effects and tolerability of gemcitabine and axitinib in a xenograft model for c-myc amplified medulloblastoma
title_fullStr	Cytotoxic effects and tolerability of gemcitabine and axitinib in a xenograft model for c-myc amplified medulloblastoma
title_full_unstemmed	Cytotoxic effects and tolerability of gemcitabine and axitinib in a xenograft model for c-myc amplified medulloblastoma
title_sort	cytotoxic effects and tolerability of gemcitabine and axitinib in a xenograft model for c-myc amplified medulloblastoma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/d110698f9bd945e084481c034902c1df
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Cytotoxic effects and tolerability of gemcitabine and axitinib in a xenograft model for c-myc amplified medulloblastoma

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