胃肠胰神经内分泌癌是一种罕见的肿瘤，没有有效的治疗方法，预后较差。用于胃肠胰神经内分泌癌研究的可靠临床前模型很少，限制了新疗法的研究。我们使用最近建立的胃肠胰腺神经内分泌癌患者异种移植模型中的肿瘤球体来系统地筛选具有不同结构的化合物，以确定可以靶向胃肠胰腺神经内分泌癌的潜在新治疗药物类别。肿瘤球体源自我们的 NEC913 和 NEC1452 胃肠胰腺神经内分泌癌癌症患者来源的异种移植模型。根据国家癌症研究所 Diversity Set VII 集合中的 885 种化合物库筛选胃肠胰腺神经内分泌癌球体。通过 AlamarBlue 测定法测量细胞活力。在鉴定出潜在的治疗化合物后，对选定的替莫唑胺和阿霉素组进行了协同筛选，并进一步分析了这些组合的 γH2AX 和磷酸化 ERK 蛋白。我们鉴定了 16 种化合物，它们可以抑制超过 75% 的胃肠胰腺神经内分泌癌球体存活。七种是酪氨酰-DNA 磷酸二酯酶 1 的抑制剂，酪氨酰-DNA 磷酸二酯酶 1 是一种与拓扑异构酶 I 复合物密切合作的 DNA 修复酶。当与替莫唑胺或多柔比星联合使用时，酪氨酰 DNA 磷酸二酯酶 1 抑制剂阿糖胞苷增加了这些药物对 NEC1452 细胞的细胞毒性作用，与单独使用替莫唑胺相比，联合治疗中 γH2AX 增加和磷酸化 ERK 减少进一步证明了这一点。 NEC913 和 NEC1452 胃肠胰腺神经内分泌癌球体系是用于药物测试的有用的临床前模型。我们的文库筛选显示，这些胃肠胰腺神经内分泌癌球体对一类以核基因组稳定性为目标的新型抗癌药物高度敏感。版权所有 © 2023 Elsevier Inc. 保留所有权利。

Gastroenteropancreatic neuroendocrine carcinomas are rare neoplasms with no effective treatments and poor prognosis. Few reliable preclinical models exist for the study of gastroenteropancreatic neuroendocrine carcinomas, limiting investigation of novel treatments. We used tumor spheroids from our recently established gastroenteropancreatic neuroendocrine carcinoma patient-derived xenograft models to systematically screen for compounds with diverse structures to identify potential new categories of therapeutic agents that can target gastroenteropancreatic neuroendocrine carcinomas.Tumor spheroids were derived from our NEC913 and NEC1452 gastroenteropancreatic neuroendocrine carcinoma patient-derived xenograft models. Gastroenteropancreatic neuroendocrine carcinoma spheroids were screened against a library of 885 compounds from the National Cancer Institute Diversity Set VII collection. Cell viability was measured via AlamarBlue assay. After identification of potential therapeutic compounds, synergy screening of a selected group with temozolomide and doxorubicin was performed, and these combinations were further analyzed for γH2AX and phosphorylated-ERK proteins.We identified 16 compounds that inhibit over 75% of gastroenteropancreatic neuroendocrine carcinoma spheroid survival. Seven are inhibitors of tyrosyl-DNA phosphodiesterase 1, a DNA repair enzyme working closely with the topoisomerase I complex. When combined with temozolomide or doxorubicin, the tyrosyl-DNA phosphodiesterase 1 inhibitor cytarabine increased the cytotoxic effects of these drugs on NEC1452 cells which was further evidenced by increasing γH2AX and decreasing phosphorylated-ERK in combination treatment compared to temozolomide alone.Both NEC913 and NEC1452 gastroenteropancreatic neuroendocrine carcinoma spheroid lines are useful preclinical models for drug testing. Our library screen revealed these gastroenteropancreatic neuroendocrine carcinoma spheroids are highly sensitive to a novel class of anti-cancer drugs that target nuclear genome stability.Copyright © 2023 Elsevier Inc. All rights reserved.