神经内分泌（类癌）肿瘤新型治疗方法的分子标志物。

Molecular markers for novel therapies in neuroendocrine (carcinoid) tumors.

机构信息

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA.

出版信息

Endocr Relat Cancer. 2010 Jun 25;17(3):623-36. doi: 10.1677/ERC-09-0318. Print 2010 Sep.

PMID:20385747

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.

摘要

神经内分泌（类癌）肿瘤（NET）是最常发生于胃肠道和支气管-肺（BP）系统的内分泌肿瘤。大多数患者就诊时已处于晚期，且治疗选择有限。我们评估了 104 例 NET（74 例），这些肿瘤的生物标志物靶向用于治疗其他类型癌症的抗癌药物。评估了表皮生长因子受体（EGFR）、干细胞因子受体（KIT）和血小板衍生生长因子受体α（PDGFRA）的激活突变，以及 KRAS 的无反应性突变。使用荧光原位杂交技术定量测定 EGFR 和 HER-2/neu 的拷贝数。进行了 EGFR、KIT、PDGFRA、生长抑素受体亚型 2A 和 5（SSTR5）、血管内皮生长因子受体 1、哺乳动物雷帕霉素靶蛋白（mTOR）、胰岛素样生长因子 1 受体（IGF1R）、热休克蛋白 90（Hsp90）和转化生长因子-β受体 1（TGFBR1）的免疫组化分析。NET 缺乏抗 HER2 反应预测的 HER2 过表达和提示伊马替尼敏感性的 KIT 和 PDGFRA 激活突变。发现了高 EGFR 非整倍体（所有病例的 20%）和 EGFR 拷贝数升高（39%），但与抗 EGFR 治疗无反应相关的 KRAS 突变很少（3%）。Hsp90、TGFBR1、IGF1R 和 SSTR5 在最大比例的肿瘤中表现出最高的免疫组化染色水平。在随后的体外研究中，抗癌药物 17-（烯丙基氨基）-17-去甲氧基格尔德霉素（17-AAG）（靶向 Hsp90）抑制 BP NET 细胞系 NCI-H727、NCI-H720 和 NCI-H835 的增殖，IC50 值分别为 70.4、310 和 788 nM；BMS-754807（靶向 IGF1R/IR）抑制生长的 IC50 值分别为 428 nM、2.8 microM 和 1 microM。在抑制生长浓度下，17-AAG（24 小时）诱导 IGF1R 表达的 NCI-H727 细胞中 EGFR 和 IGF1R 的丧失，BMS-754807（24 小时）抑制组成性 IGF1R 自身磷酸化。我们的研究结果支持进一步研究 Hsp90、IGF1R 和 EGFR 作为某些 NET 开发新抗癌治疗的靶点。