title: Molecular markers for novel therapeutic strategies in pancreatic endocrine tumors.
abstract: OBJECTIVE
  Pancreatic endocrine tumors (PETs) share numerous features with gastrointestinal neuroendocrine (carcinoid) tumors. Targets of novel therapeutic strategies previously assessed in carcinoid tumors were analyzed in PETs (44 cases).
  
  
  METHODS
  Activating mutations in EGFR, KIT, and PDGFRA and nonresponse mutations in KRAS were evaluated. Copy number of EGFR and HER-2/neu was quantified by fluorescence in situ hybridization. Expression of EGFR, PDGFRA, VEGFR1, TGFBR1, Hsp90, SSTR2A, SSTR5, IGF1R, mTOR, and MGMT was measured immunohistochemically.
  
  
  RESULTS
  Elevated EGFR copy number was found in 38% of cases but no KRAS nonresponse mutations. VEGFR1, TGFBR1, PDGFRA, SSTR5, SSTR2A, and IGF1R exhibited the highest levels of expression in the largest percentages of PETs.Anticancer drugs BMS-754807 (selective for IGF1R/IR), 17-(allylamino)-17-demethoxygeldanamycin (17-AAG, targeting Hsp90), and axitinib (directed toward VEGFR1-3/PDGFRA-B/KIT) induced growth inhibition of human QGP-1 PET cells with IC50 values (nM) of 273, 723, and 743, respectively. At growth-inhibiting concentrations, BMS-754807 inhibited IGF1R phosphorylation; 17-AAG induced loss of EGFR, IGF1R, and VEGFR2; and axitinib increased p21(CDKN1A) expression without inhibiting VEGFR2 phosphorylation.
  
  
  CONCLUSIONS
  Results encourage further research into multidrug strategies incorporating inhibitors targeting IGF1R or Hsp90 and into studies of axitinib combined with conventional chemotherapeutics toxic to tumor cells in persistent growth arrest.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Gilbert
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Adhikari
authors.forename: Ricardo V
authors.initials: RV
authors.lastname: Lloyd
authors.forename: Thorvardur R
authors.initials: TR
authors.lastname: Halfdanarson
authors.forename: Michael H
authors.initials: MH
authors.lastname: Muders
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
mesh_terms: D000077784:Axitinib; D016227:Benzoquinones / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002276:Carcinoid Tumor / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004358:Drug Therapy / Q000379:methods*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007191:Indazoles / Q000627:therapeutic use; D047029:Lactams, Macrocyclic / Q000627:therapeutic use; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D011720:Pyrazoles / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D014227:Triazines / Q000627:therapeutic use; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000077784:Axitinib; D016227:Benzoquinones; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D018841:HSP90 Heat-Shock Proteins; D007093:Imidazoles; D007191:Indazoles; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D019009:Proto-Oncogene Proteins c-kit; D016283:Proto-Oncogene Proteins p21(ras); D011720:Pyrazoles; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D020796:Receptor, Platelet-Derived Growth Factor alpha; D000077293:Receptor, Transforming Growth Factor-beta Type I; D017481:Receptors, Somatostatin; D018125:Receptors, Transforming Growth Factor beta; D014227:Triazines; D040281:Vascular Endothelial Growth Factor Receptor-1; D018631:ras Proteins; C545990:BMS 754807; C117307:KRAS protein, human; C112765:tanespimycin; C094573:somatostatin receptor 5; C093733:somatostatin receptor 2; C000625841:TGFBR1 protein, human