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.

译文

目的:胰腺内分泌肿瘤(PET)与胃肠道神经内分泌(类癌)肿瘤具有许多特征。以前在类癌肿瘤中评估过的新治疗策略的靶标已在PET(44例)中进行了分析。
方法:评估EGFR,KIT和PDGFRA的激活突变以及KRAS的无应答突变。通过荧光原位杂交定量EGFR和HER-2 / neu的拷贝数。免疫组织化学法检测EGFR,PDGFRA,VEGFR1,TGFBR1,Hsp90,SSTR2A,SSTR5,IGF1R,mTOR和MGMT的表达。
结果:38%的病例发现EGFR拷贝数升高,但没有KRAS无反应突变。 VEGFR1,TGFBR1,PDGFRA,SSTR5,SSTR2A和IGF1R在最大百分比的PET中表现出最高的表达水平。抗癌药BMS-754807(对IGF1R / IR选择性),17-(烯丙胺基)-17-去甲氧基格尔德霉素(17-靶向Hsp90的AAG和axitinib(针对VEGFR1-3 / PDGFRA-B / KIT)诱导人QGP-1 PET细胞的生长抑制,IC50值(nM)分别为273、723和743。在抑制生长的浓度下,BMS-754807抑制了IGF1R磷酸化。 17-AAG诱导的EGFR,IGF1R和VEGFR2丢失;阿昔替尼在不抑制VEGFR2磷酸化的情况下增加p21(CDKN1A)的表达。
结论:结果鼓励对结合靶向IGF1R或Hsp90的抑制剂的多药策略和阿昔替尼与常规化学治疗药物联合治疗对持续生长停滞有毒的肿瘤细胞进行进一步研究。

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