PURPOSE Pancreatic neuroendocrine tumors (pNETs) are uncommon malignancies noted for their propensity to metastasize and comparatively favorable prognosis. Although both the treatment options and clinical outcomes have improved in the past decades, most patients will die of metastatic disease. New systemic therapies are needed. EXPERIMENTAL DESIGN Tissues were obtained from 43 patients with well-differentiated pNETs undergoing surgery. Gene expression was compared between primary tumors versus liver and lymph node metastases using RNA-Seq. Genes that were selectively elevated at only one metastatic site were filtered out to reduce tissue-specific effects. Ingenuity pathway analysis (IPA) and the Connectivity Map (CMap) identified drugs likely to antagonize metastasis-specific targets. The biological activity of top identified agents was tested in vitro using two pNET cell lines (BON-1 and QGP-1). RESULTS A total of 902 genes were differentially expressed in pNET metastases compared with primary tumors, 626 of which remained in the common metastatic profile after filtering. Analysis with IPA and CMap revealed altered activity of factors involved in survival and proliferation, and identified drugs targeting those pathways, including inhibitors of mTOR, PI3K, MEK, TOP2A, protein kinase C, NF-kB, cyclin-dependent kinase, and histone deacetylase. Inhibitors of MEK and TOP2A were consistently the most active compounds. CONCLUSIONS We employed a complementary bioinformatics approach to identify novel therapeutics for pNETs by analyzing gene expression in metastatic tumors. The potential utility of these drugs was confirmed by in vitro cytotoxicity assays, suggesting drugs targeting MEK and TOP2A may be highly efficacious against metastatic pNETs. This is a promising strategy for discovering more effective treatments for patients with pNETs.

中文翻译：

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基因表达签名确定转移性胰腺神经内分泌肿瘤的新型疗法。

目的胰腺神经内分泌肿瘤（pNETs）是常见的恶性肿瘤，因其易于转移且预后相对较好。尽管在过去的几十年中，治疗选择和临床结果均得到了改善，但大多数患者将死于转移性疾病。需要新的全身疗法。实验设计从43例分化良好的pNET接受手术的患者中获取组织。使用RNA-Seq比较了原发性肿瘤与肝和淋巴结转移之间的基因表达。将仅在一个转移位点选择性升高的基因滤出以减少组织特异性作用。独创性途径分析（IPA）和连通性图（CMap）确定了可能拮抗转移特异性靶标的药物。使用两种pNET细胞系（BON-1和QGP-1）在体外测试了被鉴定最多的药物的生物活性。结果与原发性肿瘤相比，pNET转移中共有902个基因差异表达，其中626个在过滤后仍保留在常见的转移谱中。使用IPA和CMap进行的分析揭示了存活和增殖相关因子的活性发生了变化，并确定了针对这些途径的药物，包括mTOR，PI3K，MEK，TOP2A，蛋白激酶C，NF-kB，细胞周期蛋白依赖性激酶和组蛋白脱乙酰酶的抑制剂。MEK和TOP2A抑制剂始终是活性最高的化合物。结论我们通过分析转移性肿瘤中的基因表达，采用了互补的生物信息学方法来鉴定用于pNET的新型疗法。这些药物的潜在效用已通过体外细胞毒性试验得到证实，这表明靶向MEK和TOP2A的药物可能对转移性pNETs非常有效。这是为pNET患者发现更有效治疗方法的有前途的策略。