PMID- 20385747
OWN - NLM
STAT- MEDLINE
DCOM- 20101012
LR  - 20220317
IS  - 1479-6821 (Electronic)
IS  - 1351-0088 (Linking)
VI  - 17
IP  - 3
DP  - 2010 Sep
TI  - Molecular markers for novel therapies in neuroendocrine (carcinoid) tumors.
PG  - 623-36
LID - 10.1677/ERC-09-0318 [doi]
AB  - 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.
FAU - Gilbert, Judith A
AU  - Gilbert JA
AD  - Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 
      Rochester, Minnesota 55905, USA.
FAU - Adhikari, Laura J
AU  - Adhikari LJ
FAU - Lloyd, Ricardo V
AU  - Lloyd RV
FAU - Rubin, Joseph
AU  - Rubin J
FAU - Haluska, Paul
AU  - Haluska P
FAU - Carboni, Joan M
AU  - Carboni JM
FAU - Gottardis, Marco M
AU  - Gottardis MM
FAU - Ames, Matthew M
AU  - Ames MM
LA  - eng
PT  - Journal Article
DEP - 20100625
PL  - England
TA  - Endocr Relat Cancer
JT  - Endocrine-related cancer
JID - 9436481
RN  - 0 (Antineoplastic Agents)
RN  - 0 (BMS 754807)
RN  - 0 (Benzoquinones)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Lactams, Macrocyclic)
RN  - 0 (Pyrazoles)
RN  - 0 (Triazines)
RN  - 4GY0AVT3L4 (tanespimycin)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents/*pharmacology
MH  - Benzoquinones/pharmacology
MH  - Biomarkers, Tumor/genetics/*metabolism
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Female
MH  - Humans
MH  - Immunohistochemistry
MH  - In Situ Hybridization, Fluorescence
MH  - Lactams, Macrocyclic/pharmacology
MH  - Male
MH  - Middle Aged
MH  - Neuroendocrine Tumors/*drug therapy/*metabolism/pathology
MH  - Polymerase Chain Reaction
MH  - Pyrazoles/pharmacology
MH  - Retrospective Studies
MH  - Tissue Array Analysis
MH  - Triazines/pharmacology
MH  - Young Adult
EDAT- 2010/04/14 06:00
MHDA- 2010/10/13 06:00
CRDT- 2010/04/14 06:00
PHST- 2010/04/14 06:00 [entrez]
PHST- 2010/04/14 06:00 [pubmed]
PHST- 2010/10/13 06:00 [medline]
AID - ERC-09-0318 [pii]
AID - 10.1677/ERC-09-0318 [doi]
PST - epublish
SO  - Endocr Relat Cancer. 2010 Jun 25;17(3):623-36. doi: 10.1677/ERC-09-0318. Print 
      2010 Sep.