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Molecular markers for novel therapeutic strategies in pancreatic endocrine tumors Gilbert JA; Adhikari LJ; Lloyd RV; Halfdanarson TR; Muders MH; Ames MMPancreas 2013[Apr]; 42 (3): 411-21OBJECTIVES: 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.|Axitinib[MESH]|Benzoquinones/therapeutic use[MESH]|Biomarkers, Tumor/antagonists & inhibitors/*genetics/metabolism[MESH]|Carcinoid Tumor/drug therapy/*genetics/metabolism[MESH]|Cell Line, Tumor[MESH]|Cell Survival/drug effects[MESH]|Drug Therapy/*methods[MESH]|ErbB Receptors/antagonists & inhibitors/genetics/metabolism[MESH]|HSP90 Heat-Shock Proteins/antagonists & inhibitors/metabolism[MESH]|Humans[MESH]|Imidazoles/therapeutic use[MESH]|Immunohistochemistry[MESH]|In Situ Hybridization, Fluorescence[MESH]|Indazoles/therapeutic use[MESH]|Lactams, Macrocyclic/therapeutic use[MESH]|Mutation[MESH]|Pancreatic Neoplasms/drug therapy/*genetics/metabolism[MESH]|Protein Kinase Inhibitors/therapeutic use[MESH]|Protein Serine-Threonine Kinases/antagonists & inhibitors/metabolism[MESH]|Proto-Oncogene Proteins c-kit/antagonists & inhibitors/genetics/metabolism[MESH]|Proto-Oncogene Proteins p21(ras)[MESH]|Proto-Oncogene Proteins/antagonists & inhibitors/genetics/metabolism[MESH]|Pyrazoles/therapeutic use[MESH]|Receptor, ErbB-2/antagonists & inhibitors/genetics/metabolism[MESH]|Receptor, IGF Type 1/antagonists & inhibitors/metabolism[MESH]|Receptor, Platelet-Derived Growth Factor alpha/antagonists & inhibitors/genetics/metabolism[MESH]|Receptor, Transforming Growth Factor-beta Type I[MESH]|Receptors, Somatostatin/antagonists & inhibitors/metabolism[MESH]|Receptors, Transforming Growth Factor beta/antagonists & inhibitors/metabolism[MESH]|Triazines/therapeutic use[MESH]|Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors/metabolism[MESH]|ras Proteins/antagonists & inhibitors/genetics/metabolism[MESH] |
