title: Molecular markers for novel therapies in neuroendocrine (carcinoid) tumors.
abstract: Neuroendocrine (carcinoid) tumors (NETs) are endocrine neoplasms occurring most frequently in gastrointestinal and bronchopulmonary (BP) systems. The majority of patients present with advanced disease for which few treatment options exist. We assessed 104 NETs (74 cases) for biomarkers targeted by anticancer drugs under development for other forms of cancer. Activating mutations were assessed in epidermal growth factor receptor (EGFR), stem cell factor receptor (KIT), and platelet-derived growth factor receptor alpha (PDGFRA), as well as non-response mutations in KRAS. Copy number of EGFR and HER-2/neu was quantified with fluorescence in situ hybridization. Immunohistochemical analyses were performed for EGFR, KIT, PDGFRA, somatostatin receptor subtypes 2A and 5 (SSTR5), vascular endothelial growth factor receptor 1, mammalian target of rapamycin (mTOR), insulin-like growth factor 1 receptor (IGF1R), heat shock protein 90 (Hsp90), and transforming growth factor-beta receptor 1 (TGFBR1). NETs lacked HER2-overexpression predictive of anti-HER2 response and KIT and PDGFRA activating mutations indicative of imatinib sensitivity. High EGFR aneusomy (20% of all cases) and elevated EGFR copy number (39%) were found, but few KRAS mutations associated with non-response to anti-EGFR therapy (3%). Hsp90, TGFBR1, IGF1R, and SSTR5 exhibited highest levels of immunohistochemical staining in the largest percents of tumors. In subsequent in vitro studies, anticancer drug 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) (targeting Hsp90) inhibited proliferation of BP NET lines NCI-H727, NCI-H720, and NCI-H835 with IC(50) values of 70.4, 310, and 788 nM respectively; BMS-754807 (targeting IGF1R/IR) inhibited growth with IC(50) values of 428 nM, 2.8 microM, and 1 microM. At growth-inhibiting concentrations, 17-AAG (24 h) induced loss of EGFR and IGF1R in the IGF1R-expressing NCI-H727 line, and BMS-754807 (24 h) inhibited constitutive IGF1R autophosphorylation. Our results support further research into Hsp90, IGF1R, and EGFR as targets for developing new anticancer therapeutics for some NETs.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 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: Joseph
authors.initials: J
authors.lastname: Rubin
authors.forename: Paul
authors.initials: P
authors.lastname: Haluska
authors.forename: Joan M
authors.initials: JM
authors.lastname: Carboni
authors.forename: Marco M
authors.initials: MM
authors.lastname: Gottardis
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011720:Pyrazoles / Q000494:pharmacology; D012189:Retrospective Studies; D046888:Tissue Array Analysis; D014227:Triazines / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C545990:BMS 754807; D016227:Benzoquinones; D014408:Biomarkers, Tumor; D047029:Lactams, Macrocyclic; D011720:Pyrazoles; D014227:Triazines; C112765:tanespimycin