Document Detail


Molecular markers for novel therapeutic strategies in pancreatic endocrine tumors.
MedLine Citation:
PMID:  23211371     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: 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:
Judith A Gilbert; Laura J Adhikari; Ricardo V Lloyd; Thorvardur R Halfdanarson; Michael H Muders; Matthew M Ames
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Pancreas     Volume:  42     ISSN:  1536-4828     ISO Abbreviation:  Pancreas     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-08-30     Revised Date:  2014-04-02    
Medline Journal Info:
Nlm Unique ID:  8608542     Medline TA:  Pancreas     Country:  United States    
Other Details:
Languages:  eng     Pagination:  411-21     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Benzoquinones / therapeutic use
Carcinoid Tumor / drug therapy,  genetics*,  metabolism
Cell Line, Tumor
Cell Survival / drug effects
Drug Therapy / methods*
HSP90 Heat-Shock Proteins / antagonists & inhibitors,  metabolism
Humans
Imidazoles / therapeutic use
Immunohistochemistry
In Situ Hybridization, Fluorescence
Indazoles / therapeutic use
Lactams, Macrocyclic / therapeutic use
Mutation
Pancreatic Neoplasms / drug therapy,  genetics*,  metabolism
Protein Kinase Inhibitors / therapeutic use
Protein-Serine-Threonine Kinases / antagonists & inhibitors,  metabolism
Proto-Oncogene Proteins / antagonists & inhibitors,  genetics,  metabolism
Proto-Oncogene Proteins c-kit / antagonists & inhibitors,  genetics,  metabolism
Pyrazoles / therapeutic use
Receptor, Epidermal Growth Factor / antagonists & inhibitors,  genetics,  metabolism
Receptor, IGF Type 1 / antagonists & inhibitors,  metabolism
Receptor, Platelet-Derived Growth Factor alpha / antagonists & inhibitors,  genetics,  metabolism
Receptor, erbB-2 / antagonists & inhibitors,  genetics,  metabolism
Receptors, Somatostatin / antagonists & inhibitors,  metabolism
Receptors, Transforming Growth Factor beta / antagonists & inhibitors,  metabolism
Triazines / therapeutic use
Tumor Markers, Biological / antagonists & inhibitors,  genetics*,  metabolism
Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors,  metabolism
ras Proteins / antagonists & inhibitors,  genetics,  metabolism
Grant Support
ID/Acronym/Agency:
CA15083/CA/NCI NIH HHS; P30 CA015083/CA/NCI NIH HHS; P50 CA102701/CA/NCI NIH HHS; P50 CA102701/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/BMS 754807; 0/Benzoquinones; 0/HSP90 Heat-Shock Proteins; 0/Imidazoles; 0/Indazoles; 0/KRAS protein, human; 0/Lactams, Macrocyclic; 0/Protein Kinase Inhibitors; 0/Proto-Oncogene Proteins; 0/Pyrazoles; 0/Receptors, Somatostatin; 0/Receptors, Transforming Growth Factor beta; 0/Triazines; 0/Tumor Markers, Biological; 0/somatostatin receptor 2; 0/somatostatin receptor 5; 4GY0AVT3L4/tanespimycin; C9LVQ0YUXG/axitinib; EC 2.7.1.11/TGF-beta type I receptor; EC 2.7.10.1/Proto-Oncogene Proteins c-kit; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.10.1/Receptor, IGF Type 1; EC 2.7.10.1/Receptor, Platelet-Derived Growth Factor alpha; EC 2.7.10.1/Receptor, erbB-2; EC 2.7.10.1/Vascular Endothelial Growth Factor Receptor-1; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 3.6.5.2/ras Proteins
Comments/Corrections

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