title: mTOR signaling in glioblastoma: lessons learned from bench to bedside.
abstract: Phosphatidyl-inositol-3 kinases (PI3Ks) constitute a family of intracellular lipid kinases that are frequently hyperactivated in glioblastoma. The PI3K complex links growth factor signaling with cellular proliferation, differentiation, metabolism, and survival. Mammalian target of rapamycin (mTOR) acts both as a downstream effector and upstream regulator of PI3K, thus highlighting its importance in glioblastoma. This review highlights laboratory and clinical evidence of mTOR's role in glioblastoma. Mechanisms of escape from mTOR inhibition are also discussed, as well as future clinical strategies of mTOR inhibition.
authors.affiliation: The David Geffen UCLA School of Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095-1732, USA.
authors.forename: David
authors.initials: D
authors.lastname: Akhavan
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases
references.citation: Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):860-8
references.pmid: 16467100
references.citation: Cancer Cell. 2002 Apr;1(3):269-77
references.pmid: 12086863
references.citation: Cell Cycle. 2010 Jan 15;9(2):211-2
references.pmid: 20023392
references.citation: Cell Metab. 2008 May;7(5):456-65
references.pmid: 18460336
references.citation: Cancer Res. 2002 Sep 1;62(17):5027-34
references.pmid: 12208757
references.citation: Nature. 2008 Oct 23;455(7216):1061-8
references.pmid: 18772890
references.citation: Nat Rev Cancer. 2003 Jan;3(1):11-22
references.pmid: 12509763
references.citation: PLoS Med. 2008 Jan 22;5(1):e8
references.pmid: 18215105
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12867-72
references.pmid: 17646646
references.citation: Cancer Res. 2007 Dec 15;67(24):11712-20
references.pmid: 18089801
references.citation: Clin Cancer Res. 2002 May;8(5):1100-6
references.pmid: 12006525
references.citation: Science. 2007 Oct 12;318(5848):287-90
references.pmid: 17872411
references.citation: PLoS Genet. 2009 Feb;5(2):e1000374
references.pmid: 19214224
references.citation: J Natl Cancer Inst. 2005 Jun 15;97(12):880-7
references.pmid: 15956649
references.citation: Cancer Cell. 2002 Mar;1(2):157-68
references.pmid: 12086874
references.citation: Sci Signal. 2009 Jan 27;2(55):ra4
references.pmid: 19176518
references.citation: Genes Dev. 2009 Jul 15;23(14):1619-24
references.pmid: 19605683
references.citation: Mol Cell. 2008 Apr 25;30(2):214-26
references.pmid: 18439900
references.citation: Cancer Res. 2008 Aug 15;68(16):6516-23
references.pmid: 18701474
references.citation: Cancer Res. 2001 Sep 15;61(18):6674-8
references.pmid: 11559533
references.citation: Nature. 2004 Mar 18;428(6980):332-7
references.pmid: 15029198
references.citation: Nat Rev Cancer. 2002 Jul;2(7):489-501
references.pmid: 12094235
references.citation: J Clin Invest. 2008 Sep;118(9):3065-74
references.pmid: 18725988
references.citation: PLoS Biol. 2007 Apr;5(4):e95
references.pmid: 17407381
references.citation: Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10320-5
references.pmid: 11504907
references.citation: Neurology. 2006 Jul 11;67(1):156-8
references.pmid: 16832099
references.citation: Cancer Res. 2006 Aug 15;66(16):7864-9
references.pmid: 16912159
references.citation: Science. 2008 Sep 26;321(5897):1807-12
references.pmid: 18772396
references.citation: Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10314-9
references.pmid: 11504908
references.citation: Neoplasia. 2005 Apr;7(4):356-68
references.pmid: 15967113
references.citation: Mol Cell. 2009 Jan 30;33(2):237-47
references.pmid: 19187764
references.citation: Cancer Res. 2003 Apr 1;63(7):1589-95
references.pmid: 12670909
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12932-7
references.pmid: 19625624
references.citation: Invest New Drugs. 2005 Aug;23(4):357-61
references.pmid: 16012795
references.citation: Endocr Relat Cancer. 2001 Sep;8(3):249-58
references.pmid: 11566616
references.citation: Cancer Res. 2005 Jun 15;65(12):5172-80
references.pmid: 15958561
references.citation: J Biol Chem. 1997 Jan 31;272(5):2927-35
references.pmid: 9006938
references.citation: Cancer Cell. 2009 Jul 7;16(1):44-54
references.pmid: 19573811
references.citation: Genes Dev. 2007 Nov 1;21(21):2683-710
references.pmid: 17974913
references.citation: Nature. 2002 Jun 27;417(6892):949-54
references.pmid: 12068308
references.citation: Nat Rev Cancer. 2009 Aug;9(8):563-75
references.pmid: 19629071
references.citation: Cancer Res. 2003 Mar 1;63(5):1106-13
references.pmid: 12615729
references.citation: Nat Med. 2004 Jun;10(6):594-601
references.pmid: 15156201
references.citation: J Clin Invest. 2007 Mar;117(3):730-8
references.pmid: 17290308
references.citation: J Neurooncol. 2010 Jan;96(2):219-30
references.pmid: 19562254
references.citation: PLoS Biol. 2009 Jan 20;7(1):e17
references.pmid: 19166270
references.citation: Oncogene. 2006 Oct 16;25(48):6436-46
references.pmid: 17041628
references.citation: J Biol Chem. 1995 Dec 22;270(51):30562-6
references.pmid: 8530489
references.citation: Circ Res. 2007 Mar 2;100(4):564-71
references.pmid: 17272808
references.citation: J Clin Oncol. 2005 Aug 10;23(23):5294-304
references.pmid: 15998902
references.citation: Cancer Res. 1997 Sep 15;57(18):4130-40
references.pmid: 9307304
references.citation: J Neurooncol. 2009 Mar;92(1):99-105
references.pmid: 19018475
references.citation: Brain Pathol. 2009 Jan;19(1):112-20
references.pmid: 19076776
references.citation: Cancer Res. 2002 Dec 15;62(24):7291-7
references.pmid: 12499272
references.citation: Curr Biol. 1997 Apr 1;7(4):261-9
references.pmid: 9094314
references.citation: Cancer Res. 2006 Feb 1;66(3):1500-8
references.pmid: 16452206
references.citation: Cancer Res. 2003 Jun 1;63(11):2742-6
references.pmid: 12782577
references.citation: Cell. 2003 Nov 26;115(5):577-90
references.pmid: 14651849
references.citation: Mol Cancer Ther. 2009 Apr;8(4):742-53
references.pmid: 19372546
references.citation: Nat Rev Cancer. 2006 Sep;6(9):729-34
references.pmid: 16915295
references.citation: Cancer Res. 2009 Apr 15;69(8):3256-61
references.pmid: 19351834
references.citation: Cell. 2009 May 29;137(5):873-86
references.pmid: 19446321
references.citation: Cancer Cell. 2006 May;9(5):341-9
references.pmid: 16697955
references.citation: Nature. 2006 May 25;441(7092):475-82
references.pmid: 16598206
references.citation: Curr Opin Genet Dev. 2007 Feb;17(1):31-9
references.pmid: 17208430
references.citation: Br J Cancer. 2009 Jan 27;100(2):370-5
references.pmid: 19165201
references.citation: N Engl J Med. 2005 Nov 10;353(19):2012-24
references.pmid: 16282176
references.citation: Sci Signal. 2009 Dec 15;2(101):ra82
references.pmid: 20009104
references.citation: Cancer Res. 2007 Sep 1;67(17):7960-5
references.pmid: 17804702
references.citation: Science. 2005 Feb 18;307(5712):1098-101
references.pmid: 15718470
references.citation: Clin Cancer Res. 2008 Jan 15;14(2):488-93
references.pmid: 18223223
references.citation: Nat Med. 2009 Jan;15(1):110-6
references.pmid: 19122659
references.citation: Mol Cancer Ther. 2007 Mar;6(3):1167-74
references.pmid: 17363510
references.citation: Mol Cancer Ther. 2008 Jul;7(7):1851-63
references.pmid: 18606717
references.citation: J Biol Chem. 2009 Mar 20;284(12):8023-32
references.pmid: 19150980
references.citation: N Engl J Med. 2005 Mar 10;352(10):987-96
references.pmid: 15758009
references.citation: Nat Rev Genet. 2006 Aug;7(8):606-19
references.pmid: 16847462
references.citation: Nat Rev Genet. 2001 Feb;2(2):120-9
references.pmid: 11253051
references.citation: Sci Signal. 2009 Apr 21;2(67):pe24
references.pmid: 19383975
references.citation: Cancer Res. 2003 Dec 1;63(23):8132-7
references.pmid: 14678966