Molecular markers for novel therapeutic strategies in pancreatic endocrine tumors

Judith A. Gilbert, Laura J. Adhikari, Ricardo V. Lloyd, Thorvardur R. Halfdanarson, Michael H. Muders, Matthew M. Ames

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)411-421
Number of pages11
JournalPancreas
Volume42
Issue number3
DOIs
StatePublished - Apr 2013
Externally publishedYes

Fingerprint

tanespimycin
Carcinoid Tumor
Neoplasms
Mutation
Growth
Phosphorylation
Therapeutics
Endocrine Cells
Neuroendocrine Tumors
Poisons
Fluorescence In Situ Hybridization
Inhibitory Concentration 50
Research
Pharmaceutical Preparations
axitinib

Keywords

  • Molecular analysis
  • Pancreatic endocrine tumors

ASJC Scopus subject areas

  • Hepatology
  • Internal Medicine
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Gilbert, J. A., Adhikari, L. J., Lloyd, R. V., Halfdanarson, T. R., Muders, M. H., & Ames, M. M. (2013). Molecular markers for novel therapeutic strategies in pancreatic endocrine tumors. Pancreas, 42(3), 411-421. https://doi.org/10.1097/MPA.0b013e31826cb243

Molecular markers for novel therapeutic strategies in pancreatic endocrine tumors. / Gilbert, Judith A.; Adhikari, Laura J.; Lloyd, Ricardo V.; Halfdanarson, Thorvardur R.; Muders, Michael H.; Ames, Matthew M.

In: Pancreas, Vol. 42, No. 3, 04.2013, p. 411-421.

Research output: Contribution to journalArticle

Gilbert, JA, Adhikari, LJ, Lloyd, RV, Halfdanarson, TR, Muders, MH & Ames, MM 2013, 'Molecular markers for novel therapeutic strategies in pancreatic endocrine tumors', Pancreas, vol. 42, no. 3, pp. 411-421. https://doi.org/10.1097/MPA.0b013e31826cb243
Gilbert JA, Adhikari LJ, Lloyd RV, Halfdanarson TR, Muders MH, Ames MM. Molecular markers for novel therapeutic strategies in pancreatic endocrine tumors. Pancreas. 2013 Apr;42(3):411-421. https://doi.org/10.1097/MPA.0b013e31826cb243
Gilbert, Judith A. ; Adhikari, Laura J. ; Lloyd, Ricardo V. ; Halfdanarson, Thorvardur R. ; Muders, Michael H. ; Ames, Matthew M. / Molecular markers for novel therapeutic strategies in pancreatic endocrine tumors. In: Pancreas. 2013 ; Vol. 42, No. 3. pp. 411-421.
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