title: Activation of mTORC1/mTORC2 signaling in pediatric low-grade glioma and pilocytic astrocytoma reveals mTOR as a therapeutic target.
abstract: BACKGROUND
  Previous studies support a role for mitogen-activated 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 differentially active in optic pathway and neurofibromatosis type 1-associated gliomas. MTOR represents a potential therapeutic target in PLGG that merits further investigation.
authors.affiliation: Corresponding Authors: Fausto J. Rodriguez, MD, Division of Neuropathology, Johns Hopkins Hospital, 1800 Orleans Street, Baltimore, MD 21231. frodrig4@jhmi.edu; eraabe2@jhmi.edu Eric H. Raabe, MD, PhD, Division of Neuropathology, Johns Hopkins Hospital, 1800 Orleans Street, Baltimore, MD 21231 (eraabe2@jhmi.edu).
authors.forename: Marianne
authors.initials: M
authors.lastname: Hütt-Cabezas
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Karajannis
authors.forename: David
authors.initials: D
authors.lastname: Zagzag
authors.forename: Smit
authors.initials: S
authors.lastname: Shah
authors.forename: Iren
authors.initials: I
authors.lastname: Horkayne-Szakaly
authors.forename: Elisabeth J
authors.initials: EJ
authors.lastname: Rushing
authors.forename: J Douglas
authors.initials: JD
authors.lastname: Cameron
authors.forename: Deepali
authors.initials: D
authors.lastname: Jain
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Eric H
authors.initials: EH
authors.lastname: Raabe
authors.forename: Fausto J
authors.initials: FJ
authors.lastname: Rodriguez
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001254:Astrocytoma / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D007223:Infant; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000378:metabolism*; D060787:Neoplasm Grading; D011379:Prognosis; D012189:Retrospective Studies; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D046912:Multiprotein Complexes; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
keywords: mTOR; neurofibromatosis; optic nerve; pediatric glioma; pilocytic astrocytoma