Combined PI3Kα-mTOR Targeting of Glioma Stem Cells

Abstract Glioblastoma (GBM) is the most common and lethal primary intrinsic tumour of the adult brain and evidence indicates disease progression is driven by glioma stem cells (GSCs). Extensive advances in the molecular characterization of GBM allowed classification into proneural, mesenchymal and c...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Frank D. Eckerdt, Jonathan B. Bell, Christopher Gonzalez, Michael S. Oh, Ricardo E. Perez, Candice Mazewski, Mariafausta Fischietti, Stewart Goldman, Ichiro Nakano, Leonidas C. Platanias
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bb07ee97883b447baba480ea2552c1ef
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:bb07ee97883b447baba480ea2552c1ef
record_format	dspace
spelling	oai:doaj.org-article:bb07ee97883b447baba480ea2552c1ef2021-12-02T13:58:13ZCombined PI3Kα-mTOR Targeting of Glioma Stem Cells10.1038/s41598-020-78788-z2045-2322https://doaj.org/article/bb07ee97883b447baba480ea2552c1ef2020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78788-zhttps://doaj.org/toc/2045-2322Abstract Glioblastoma (GBM) is the most common and lethal primary intrinsic tumour of the adult brain and evidence indicates disease progression is driven by glioma stem cells (GSCs). Extensive advances in the molecular characterization of GBM allowed classification into proneural, mesenchymal and classical subtypes, and have raised expectations these insights may predict response to targeted therapies. We utilized GBM neurospheres that display GSC characteristics and found activation of the PI3K/AKT pathway in sphere-forming cells. The PI3Kα selective inhibitor alpelisib blocked PI3K/AKT activation and inhibited spheroid growth, suggesting an essential role for the PI3Kα catalytic isoform. p110α expression was highest in the proneural subtype and this was associated with increased phosphorylation of AKT. Further, employing the GBM BioDP, we found co-expression of PIK3CA with the neuronal stem/progenitor marker NES was associated with poor prognosis in PN GBM patients, indicating a unique role for PI3Kα in PN GSCs. Alpelisib inhibited GSC neurosphere growth and these effects were more pronounced in GSCs of the PN subtype. The antineoplastic effects of alpelisib were substantially enhanced when combined with pharmacologic mTOR inhibition. These findings identify the alpha catalytic PI3K isoform as a unique therapeutic target in proneural GBM and suggest that pharmacological mTOR inhibition may sensitize GSCs to selective PI3Kα inhibition.Frank D. EckerdtJonathan B. BellChristopher GonzalezMichael S. OhRicardo E. PerezCandice MazewskiMariafausta FischiettiStewart GoldmanIchiro NakanoLeonidas C. PlataniasNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-11 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Frank D. Eckerdt Jonathan B. Bell Christopher Gonzalez Michael S. Oh Ricardo E. Perez Candice Mazewski Mariafausta Fischietti Stewart Goldman Ichiro Nakano Leonidas C. Platanias Combined PI3Kα-mTOR Targeting of Glioma Stem Cells
description	Abstract Glioblastoma (GBM) is the most common and lethal primary intrinsic tumour of the adult brain and evidence indicates disease progression is driven by glioma stem cells (GSCs). Extensive advances in the molecular characterization of GBM allowed classification into proneural, mesenchymal and classical subtypes, and have raised expectations these insights may predict response to targeted therapies. We utilized GBM neurospheres that display GSC characteristics and found activation of the PI3K/AKT pathway in sphere-forming cells. The PI3Kα selective inhibitor alpelisib blocked PI3K/AKT activation and inhibited spheroid growth, suggesting an essential role for the PI3Kα catalytic isoform. p110α expression was highest in the proneural subtype and this was associated with increased phosphorylation of AKT. Further, employing the GBM BioDP, we found co-expression of PIK3CA with the neuronal stem/progenitor marker NES was associated with poor prognosis in PN GBM patients, indicating a unique role for PI3Kα in PN GSCs. Alpelisib inhibited GSC neurosphere growth and these effects were more pronounced in GSCs of the PN subtype. The antineoplastic effects of alpelisib were substantially enhanced when combined with pharmacologic mTOR inhibition. These findings identify the alpha catalytic PI3K isoform as a unique therapeutic target in proneural GBM and suggest that pharmacological mTOR inhibition may sensitize GSCs to selective PI3Kα inhibition.
format	article
author	Frank D. Eckerdt Jonathan B. Bell Christopher Gonzalez Michael S. Oh Ricardo E. Perez Candice Mazewski Mariafausta Fischietti Stewart Goldman Ichiro Nakano Leonidas C. Platanias
author_facet	Frank D. Eckerdt Jonathan B. Bell Christopher Gonzalez Michael S. Oh Ricardo E. Perez Candice Mazewski Mariafausta Fischietti Stewart Goldman Ichiro Nakano Leonidas C. Platanias
author_sort	Frank D. Eckerdt
title	Combined PI3Kα-mTOR Targeting of Glioma Stem Cells
title_short	Combined PI3Kα-mTOR Targeting of Glioma Stem Cells
title_full	Combined PI3Kα-mTOR Targeting of Glioma Stem Cells
title_fullStr	Combined PI3Kα-mTOR Targeting of Glioma Stem Cells
title_full_unstemmed	Combined PI3Kα-mTOR Targeting of Glioma Stem Cells
title_sort	combined pi3kα-mtor targeting of glioma stem cells
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/bb07ee97883b447baba480ea2552c1ef
work_keys_str_mv	AT frankdeckerdt combinedpi3kamtortargetingofgliomastemcells AT jonathanbbell combinedpi3kamtortargetingofgliomastemcells AT christophergonzalez combinedpi3kamtortargetingofgliomastemcells AT michaelsoh combinedpi3kamtortargetingofgliomastemcells AT ricardoeperez combinedpi3kamtortargetingofgliomastemcells AT candicemazewski combinedpi3kamtortargetingofgliomastemcells AT mariafaustafischietti combinedpi3kamtortargetingofgliomastemcells AT stewartgoldman combinedpi3kamtortargetingofgliomastemcells AT ichironakano combinedpi3kamtortargetingofgliomastemcells AT leonidascplatanias combinedpi3kamtortargetingofgliomastemcells
_version_	1718392224233816064

Combined PI3Kα-mTOR Targeting of Glioma Stem Cells

Ejemplares similares