Activation of mtorc1/mtorc2 signaling in pediatric low-Grade glioma and pilocytic astrocytoma reveals mtor as a therapeutic target

Marianne Hütt-Cabezas, Matthias A. Karajannis, David Zagzag, Smit Shah, Iren Horkayne-Szakaly, Elisabeth J. Rushing, J. Douglas Cameron, Deepali Jain, Charles G Eberhart, Eric Raabe, Fausto J Rodriguez

Research output: Contribution to journalArticle

Abstract

Background. Previous studiessupport a role for mitogenactivated protein kinase pathway signaling, and more recently Akt/mammalian target of rapamycin (mTOR), in pediatric low-grade glioma (PLGG), including pilocytic astrocytoma (PA). Here we further evaluate the role of the mTORC1/mTORC2 pathway in order to better direct pharmacologic blockade in these common childhood tumors. Methods. We studied 177 PLGGs and PAs using immunohistochemistry and tested the effect of mTOR blockade on 2 PLGG cell lines (Res186 and Res259) in vitro. Results. Moderate (2+) to strong (3+) immunostaining was observed for pS6 in 107/177 (59%) PAs and other PLGGs, while p4EBP1 was observed in 35/115 (30%), pElF4G in 66/112 (59%), mTOR (total) in 53/113 (47%), RAPTOR (mTORC1 component) in 64/102 (63%), RICTOR (mTORC2 component) in 48/101 (48%), and pAkt (S473) in 63/103 (61%). Complete phosphatase and tensin homolog protein loss was identified in only 7/101 (7%) of cases. In PA of the optic pathways, compared with other anatomic sites, there was increased immunoreactivity for pS6, pElF4G, mTOR(total), RICTOR, and pAkt (P <.05).We also observed increased pS6 (P = .01), p4EBP1 (P = .029), and RICTOR(P = .05) in neurofibromatosis type 1 compared with sporadic tumors. Treatment of the PLGG cell lines Res186 (PA derived) and Res259 (diffuse astrocytoma derived) with the rapalog MK8669 (ridaforolimus) led to decreased mTOR pathway activation and growth. Conclusions. These findings suggest that the mTOR pathway is active in PLGG but varies by clinicopathologic subtype. Additionally, our data suggest that mTORC2 is differentiallyactive in opticpathwayandneurofibromatosis type1- associatedgliomas.MTORrepresents apotential therapeutic target inPLGGthatmerits further investigation.

Original languageEnglish (US)
Pages (from-to)1604-1614
Number of pages11
JournalNeuro-Oncology
Volume15
Issue number12
DOIs
StatePublished - 2013

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Astrocytoma
Sirolimus
Glioma
Pediatrics
Therapeutics
Cell Line
Neurofibromatosis 1
Phosphoric Monoester Hydrolases
Protein Kinases
Neoplasms
Immunohistochemistry
Growth
TOR complex 2
Proteins

Keywords

  • MTOR
  • Neurofibromatosis
  • Optic nerve
  • Pediatric glioma
  • Pilocytic astrocytoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Clinical Neurology

Cite this

Activation of mtorc1/mtorc2 signaling in pediatric low-Grade glioma and pilocytic astrocytoma reveals mtor as a therapeutic target. / Hütt-Cabezas, Marianne; Karajannis, Matthias A.; Zagzag, David; Shah, Smit; Horkayne-Szakaly, Iren; Rushing, Elisabeth J.; Cameron, J. Douglas; Jain, Deepali; Eberhart, Charles G; Raabe, Eric; Rodriguez, Fausto J.

In: Neuro-Oncology, Vol. 15, No. 12, 2013, p. 1604-1614.

Research output: Contribution to journalArticle

Hütt-Cabezas, M, Karajannis, MA, Zagzag, D, Shah, S, Horkayne-Szakaly, I, Rushing, EJ, Cameron, JD, Jain, D, Eberhart, CG, Raabe, E & Rodriguez, FJ 2013, 'Activation of mtorc1/mtorc2 signaling in pediatric low-Grade glioma and pilocytic astrocytoma reveals mtor as a therapeutic target', Neuro-Oncology, vol. 15, no. 12, pp. 1604-1614. https://doi.org/10.1093/neuonc/not132
Hütt-Cabezas, Marianne ; Karajannis, Matthias A. ; Zagzag, David ; Shah, Smit ; Horkayne-Szakaly, Iren ; Rushing, Elisabeth J. ; Cameron, J. Douglas ; Jain, Deepali ; Eberhart, Charles G ; Raabe, Eric ; Rodriguez, Fausto J. / Activation of mtorc1/mtorc2 signaling in pediatric low-Grade glioma and pilocytic astrocytoma reveals mtor as a therapeutic target. In: Neuro-Oncology. 2013 ; Vol. 15, No. 12. pp. 1604-1614.
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abstract = "Background. Previous studiessupport a role for mitogenactivated protein kinase pathway signaling, and more recently Akt/mammalian target of rapamycin (mTOR), in pediatric low-grade glioma (PLGG), including pilocytic astrocytoma (PA). Here we further evaluate the role of the mTORC1/mTORC2 pathway in order to better direct pharmacologic blockade in these common childhood tumors. Methods. We studied 177 PLGGs and PAs using immunohistochemistry and tested the effect of mTOR blockade on 2 PLGG cell lines (Res186 and Res259) in vitro. Results. Moderate (2+) to strong (3+) immunostaining was observed for pS6 in 107/177 (59{\%}) PAs and other PLGGs, while p4EBP1 was observed in 35/115 (30{\%}), pElF4G in 66/112 (59{\%}), mTOR (total) in 53/113 (47{\%}), RAPTOR (mTORC1 component) in 64/102 (63{\%}), RICTOR (mTORC2 component) in 48/101 (48{\%}), and pAkt (S473) in 63/103 (61{\%}). Complete phosphatase and tensin homolog protein loss was identified in only 7/101 (7{\%}) of cases. In PA of the optic pathways, compared with other anatomic sites, there was increased immunoreactivity for pS6, pElF4G, mTOR(total), RICTOR, and pAkt (P <.05).We also observed increased pS6 (P = .01), p4EBP1 (P = .029), and RICTOR(P = .05) in neurofibromatosis type 1 compared with sporadic tumors. Treatment of the PLGG cell lines Res186 (PA derived) and Res259 (diffuse astrocytoma derived) with the rapalog MK8669 (ridaforolimus) led to decreased mTOR pathway activation and growth. Conclusions. These findings suggest that the mTOR pathway is active in PLGG but varies by clinicopathologic subtype. Additionally, our data suggest that mTORC2 is differentiallyactive in opticpathwayandneurofibromatosis type1- associatedgliomas.MTORrepresents apotential therapeutic target inPLGGthatmerits further investigation.",
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T1 - Activation of mtorc1/mtorc2 signaling in pediatric low-Grade glioma and pilocytic astrocytoma reveals mtor as a therapeutic target

AU - Hütt-Cabezas, Marianne

AU - Karajannis, Matthias A.

AU - Zagzag, David

AU - Shah, Smit

AU - Horkayne-Szakaly, Iren

AU - Rushing, Elisabeth J.

AU - Cameron, J. Douglas

AU - Jain, Deepali

AU - Eberhart, Charles G

AU - Raabe, Eric

AU - Rodriguez, Fausto J

PY - 2013

Y1 - 2013

N2 - Background. Previous studiessupport a role for mitogenactivated protein kinase pathway signaling, and more recently Akt/mammalian target of rapamycin (mTOR), in pediatric low-grade glioma (PLGG), including pilocytic astrocytoma (PA). Here we further evaluate the role of the mTORC1/mTORC2 pathway in order to better direct pharmacologic blockade in these common childhood tumors. Methods. We studied 177 PLGGs and PAs using immunohistochemistry and tested the effect of mTOR blockade on 2 PLGG cell lines (Res186 and Res259) in vitro. Results. Moderate (2+) to strong (3+) immunostaining was observed for pS6 in 107/177 (59%) PAs and other PLGGs, while p4EBP1 was observed in 35/115 (30%), pElF4G in 66/112 (59%), mTOR (total) in 53/113 (47%), RAPTOR (mTORC1 component) in 64/102 (63%), RICTOR (mTORC2 component) in 48/101 (48%), and pAkt (S473) in 63/103 (61%). Complete phosphatase and tensin homolog protein loss was identified in only 7/101 (7%) of cases. In PA of the optic pathways, compared with other anatomic sites, there was increased immunoreactivity for pS6, pElF4G, mTOR(total), RICTOR, and pAkt (P <.05).We also observed increased pS6 (P = .01), p4EBP1 (P = .029), and RICTOR(P = .05) in neurofibromatosis type 1 compared with sporadic tumors. Treatment of the PLGG cell lines Res186 (PA derived) and Res259 (diffuse astrocytoma derived) with the rapalog MK8669 (ridaforolimus) led to decreased mTOR pathway activation and growth. Conclusions. These findings suggest that the mTOR pathway is active in PLGG but varies by clinicopathologic subtype. Additionally, our data suggest that mTORC2 is differentiallyactive in opticpathwayandneurofibromatosis type1- associatedgliomas.MTORrepresents apotential therapeutic target inPLGGthatmerits further investigation.

AB - Background. Previous studiessupport a role for mitogenactivated protein kinase pathway signaling, and more recently Akt/mammalian target of rapamycin (mTOR), in pediatric low-grade glioma (PLGG), including pilocytic astrocytoma (PA). Here we further evaluate the role of the mTORC1/mTORC2 pathway in order to better direct pharmacologic blockade in these common childhood tumors. Methods. We studied 177 PLGGs and PAs using immunohistochemistry and tested the effect of mTOR blockade on 2 PLGG cell lines (Res186 and Res259) in vitro. Results. Moderate (2+) to strong (3+) immunostaining was observed for pS6 in 107/177 (59%) PAs and other PLGGs, while p4EBP1 was observed in 35/115 (30%), pElF4G in 66/112 (59%), mTOR (total) in 53/113 (47%), RAPTOR (mTORC1 component) in 64/102 (63%), RICTOR (mTORC2 component) in 48/101 (48%), and pAkt (S473) in 63/103 (61%). Complete phosphatase and tensin homolog protein loss was identified in only 7/101 (7%) of cases. In PA of the optic pathways, compared with other anatomic sites, there was increased immunoreactivity for pS6, pElF4G, mTOR(total), RICTOR, and pAkt (P <.05).We also observed increased pS6 (P = .01), p4EBP1 (P = .029), and RICTOR(P = .05) in neurofibromatosis type 1 compared with sporadic tumors. Treatment of the PLGG cell lines Res186 (PA derived) and Res259 (diffuse astrocytoma derived) with the rapalog MK8669 (ridaforolimus) led to decreased mTOR pathway activation and growth. Conclusions. These findings suggest that the mTOR pathway is active in PLGG but varies by clinicopathologic subtype. Additionally, our data suggest that mTORC2 is differentiallyactive in opticpathwayandneurofibromatosis type1- associatedgliomas.MTORrepresents apotential therapeutic target inPLGGthatmerits further investigation.

KW - MTOR

KW - Neurofibromatosis

KW - Optic nerve

KW - Pediatric glioma

KW - Pilocytic astrocytoma

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DO - 10.1093/neuonc/not132

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