Molecular markers for novel therapies in neuroendocrine (carcinoid) tumors

Judith A. Gilbert, Laura J. Adhikari, Ricardo V. Lloyd, Joseph Rubin, Paul Haluska, Joan M. Carboni, Marco M. Gottardis, Matthew M. Ames

Research output: Contribution to journalArticle

44 Citations (Scopus)

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-b 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 IC50 values of 70.4, 310, and 788 nM respectively; BMS-754807 (targeting IGF1R/IR) inhibited growth with IC50 values of 428 nM, 2.8 mM, and 1 mM. 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.

Original languageEnglish (US)
Pages (from-to)623-636
Number of pages14
JournalEndocrine-Related Cancer
Volume17
Issue number3
DOIs
StatePublished - 2010

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Neuroendocrine Tumors
Somatomedin Receptors
Carcinoid Tumor
Epidermal Growth Factor Receptor
HSP90 Heat-Shock Proteins
Platelet-Derived Growth Factor alpha Receptor
tanespimycin
Mutation
Growth Factor Receptors
Transforming Growth Factors
Therapeutics
Inhibitory Concentration 50
Proto-Oncogene Proteins c-kit
Vascular Endothelial Growth Factor Receptor-1
Neoplasms
Sirolimus
Growth
Fluorescence In Situ Hybridization
Pharmaceutical Preparations
Biomarkers

ASJC Scopus subject areas

  • Endocrinology
  • Oncology
  • Cancer Research
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

Gilbert, J. A., Adhikari, L. J., Lloyd, R. V., Rubin, J., Haluska, P., Carboni, J. M., ... Ames, M. M. (2010). Molecular markers for novel therapies in neuroendocrine (carcinoid) tumors. Endocrine-Related Cancer, 17(3), 623-636. https://doi.org/10.1677/ERC-09-0318

Molecular markers for novel therapies in neuroendocrine (carcinoid) tumors. / Gilbert, Judith A.; Adhikari, Laura J.; Lloyd, Ricardo V.; Rubin, Joseph; Haluska, Paul; Carboni, Joan M.; Gottardis, Marco M.; Ames, Matthew M.

In: Endocrine-Related Cancer, Vol. 17, No. 3, 2010, p. 623-636.

Research output: Contribution to journalArticle

Gilbert, JA, Adhikari, LJ, Lloyd, RV, Rubin, J, Haluska, P, Carboni, JM, Gottardis, MM & Ames, MM 2010, 'Molecular markers for novel therapies in neuroendocrine (carcinoid) tumors', Endocrine-Related Cancer, vol. 17, no. 3, pp. 623-636. https://doi.org/10.1677/ERC-09-0318
Gilbert JA, Adhikari LJ, Lloyd RV, Rubin J, Haluska P, Carboni JM et al. Molecular markers for novel therapies in neuroendocrine (carcinoid) tumors. Endocrine-Related Cancer. 2010;17(3):623-636. https://doi.org/10.1677/ERC-09-0318
Gilbert, Judith A. ; Adhikari, Laura J. ; Lloyd, Ricardo V. ; Rubin, Joseph ; Haluska, Paul ; Carboni, Joan M. ; Gottardis, Marco M. ; Ames, Matthew M. / Molecular markers for novel therapies in neuroendocrine (carcinoid) tumors. In: Endocrine-Related Cancer. 2010 ; Vol. 17, No. 3. pp. 623-636.
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