title: Phospho-mTOR is not upregulated in metastatic SDHB paragangliomas.
abstract: BACKGROUND
  Pheochromocytomas (PCCs)/paragangliomas (PGLs) are neuroendocrine tumours that may cause arrhythmia and death if untreated. Treatment for patients with metastatic tumours is lacking. As new PCC/PGL susceptibility genes are discovered that are associated with the mTOR pathway, treatment targets focusing on this pathway are being intensively explored.
  
  
  METHODS
  Twenty-one human PCC/PGLs were analysed from two tertiary care centres. Immunohistochemistry (IHC) analysis was performed for phospho-mTOR (pmTOR), phospho-S6K (pS6K), phosphoinositide 3-kinase (PI3K), phospho-4EBP1 (p4EBP1), HIF1α and MIB-1 in 6 metastatic SDHB PCC/PGLs, 15 nonmetastatic PCC/PGLs, (including 1 TMEM127 PCC and 1 nonmetastatic SDHB PGL) and 6 normal adrenal medullas. The product of the intensity of stain and percentage of cells stained was calculated as an H score.
  
  
  RESULTS
  Using a two-sample t-test and paired t-test, pmTOR and pS6K had significantly higher H scores in nonmetastatic PCC/PGLs than in metastatic SDHB PCC/PGLs. HIF1α had significantly higher H scores in metastatic SDHB PCC/PGLs compared with nonmetastatic PCC/PGLs and normal adrenal medulla. No difference in H scores was seen with p4EBP1, PI3K and MIB-1 when comparing metastatic SDHB PCC/PGLs and nonmetastatic PCC/PGLs. Significantly higher difference in pS6K was seen in normal adrenal medullas compared to nonmetastatic PCC/PGLs and metastatic SDHB PCC/PGLs.
  
  
  CONCLUSIONS
  The present results suggest that the use of mTOR inhibitors alone for metastatic SDHB PCC/PGLs may not achieve good therapeutic efficacy in patients.
authors.affiliation: Department of Internal Medicine, VA North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
authors.forename: Hans K
authors.initials: HK
authors.lastname: Ghayee
authors.forename: Alessio
authors.initials: A
authors.lastname: Giubellino
authors.forename: Arielle
authors.initials: A
authors.lastname: Click
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.forename: Alana
authors.initials: A
authors.lastname: Christie
authors.forename: Xian-Jin
authors.initials: XJ
authors.lastname: Xie
authors.forename: Victoria
authors.initials: V
authors.lastname: Martucci
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
authors.forename: Rhonda F
authors.initials: RF
authors.lastname: Souza
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000313:Adrenal Medulla / Q000378:metabolism; D018797:Cell Cycle Proteins; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D009154:Mutation / Q000235:genetics; D009362:Neoplasm Metastasis; D010235:Paraganglioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D019893:Ribosomal Protein S6 Kinases; D013385:Succinate Dehydrogenase; D058570:TOR Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; C087000:EIF4EBP1 protein, human; C497442:HIF1A protein, human; C101633:PA2G4 protein, human; C108095:SDHB protein, human; C513496:MIB1 ligase, human; C546842:MTOR protein, human
keywords: Paraganglioma; SDHB; pmTOR
references.citation: Genes Dev. 2004 Dec 1;18(23):2893-904
references.pmid: 15545625
references.citation: Cell. 2012 Apr 13;149(2):274-93
references.pmid: 22500797
references.citation: Hum Mol Genet. 2010 Aug 1;19(15):3011-20
references.pmid: 20484225
references.citation: Endocr Relat Cancer. 2011 Dec 01;18(6):R253-76
references.pmid: 22041710
references.citation: Horm Metab Res. 2009 Sep;41(9):697-702
references.pmid: 19424940
references.citation: Endocrinology. 2013 Feb;154(2):646-55
references.pmid: 23307788
references.citation: J Clin Oncol. 2008 Sep 10;26(26):4311-8
references.pmid: 18779618
references.citation: Semin Oncol. 2010 Dec;37(6):627-37
references.pmid: 21167381
references.citation: Urology. 2013 Mar;81(3):581-6
references.pmid: 23290145
references.citation: Cold Spring Harb Perspect Biol. 2012 Feb 01;4(2):
references.pmid: 22129599
references.citation: J Endocrinol Invest. 2008 May;31(5):450-8
references.pmid: 18560264
references.citation: Nat Chem Biol. 2011 Jan;7(1):9-17
references.pmid: 21164513
references.citation: Nat Genet. 2012 Jun 10;44(7):751-9
references.pmid: 22683710
references.citation: Nat Genet. 2011 Jun 19;43(7):663-7
references.pmid: 21685915
references.citation: Nat Rev Neurosci. 2002 Jul;3(7):531-41
references.pmid: 12094209
references.citation: Science. 2009 Aug 28;325(5944):1139-42
references.pmid: 19628817
references.citation: N Engl J Med. 2011 Feb 10;364(6):514-23
references.pmid: 21306238
references.citation: Cancer Cell. 2004 Jan;5(1):79-90
references.pmid: 14749128
references.citation: N Engl J Med. 2012 Sep 6;367(10):922-30
references.pmid: 22931260
references.citation: Nat Genet. 2010 Mar;42(3):229-33
references.pmid: 20154675
references.citation: Genes Dev. 2004 Dec 1;18(23):2879-92
references.pmid: 15545626
references.citation: Lancet. 2005 Aug 20-26;366(9486):665-75
references.pmid: 16112304