University of Alabama at Birmingham School of Medicine, AL.
Department of Surgery, University of Alabama at Birmingham School of Medicine, AL.
Surgery. 2020 Jan;167(1):197-203. doi: 10.1016/j.surg.2019.04.073. Epub 2019 Sep 19.
As patient-derived xenografts and other preclinical models of neuroendocrine tumors for testing personalized therapeutics are lacking, we have developed a perfused, 3D bioreactor model to culture tumor surrogates from patient-derived neuroendocrine tumors. This work evaluates the duration of surrogate culture and surrogate response to a novel antibody-drug conjugate.
Twenty-seven patient-derived neuroendocrine tumors were cultured. Histologic sections of a pancreatic neuroendocrine tumor xenograft (BON-1) tumor were assessed for SSTR2 expression before tumor implantation into 2 bioreactors. One surrogate was treated with an antibody-drug conjugate composed of an anti-mitotic Monomethyl auristatin-E linked to a somatostatin receptor 2 antibody. Viability and therapeutic response were assessed by pre-imaging incubation with IR-783 and the RealTime-Glo AnnexinV Apoptosis and Necrosis Assay (Promega Corporation, Madison, WI) over 6 days. A primary human pancreatic neuroendocrine tumor was evaluated similarly.
Mean surrogate growth duration was 34.8 days. Treated BON-1 surrogates exhibited less proliferation (1.2 vs 1.9-fold) and greater apoptosis (1.5 vs 1.1-fold) than controls, whereas treated patient-derived neuroendocrine tumor bioreactors exhibited greater degrees of apoptosis (13- vs 9-fold) and necrosis (2.5- vs 1.6-fold).
Patient-derived neuroendocrine tumor surrogates can be cultured reliably within the bioreactor. This model can be used to evaluate the efficacy of antibody-guided chemotherapy ex vivo and may be useful for predicting clinical responses.
由于缺乏用于测试个性化治疗的神经内分泌肿瘤患者来源异种移植物和其他临床前模型，我们开发了一种灌注的 3D 生物反应器模型，以培养来自患者来源的神经内分泌肿瘤的肿瘤替代物。这项工作评估了替代物培养的持续时间以及替代物对新型抗体药物偶联物的反应。
培养了 27 个患者来源的神经内分泌肿瘤。在将胰腺神经内分泌肿瘤异种移植物（BON-1）肿瘤的组织学切片植入 2 个生物反应器之前，评估了 SSTR2 的表达。一种替代物用一种由抗有丝分裂单甲基奥瑞他汀 E 与生长抑素受体 2 抗体连接而成的抗体药物偶联物进行治疗。通过在 6 天内用 IR-783 进行预成像孵育以及使用 RealTime-Glo AnnexinV 凋亡和坏死测定法（Promega Corporation，Madison，WI）评估活力和治疗反应。类似地评估了原发性人胰腺神经内分泌肿瘤。
平均替代物生长持续时间为 34.8 天。与对照组相比，经处理的 BON-1 替代物的增殖减少（1.2 倍对 1.9 倍），凋亡增加（1.5 倍对 1.1 倍），而经处理的患者来源的神经内分泌肿瘤生物反应器的凋亡（13 倍对 9 倍）和坏死（2.5 倍对 1.6 倍）程度更大。
患者来源的神经内分泌肿瘤替代物可以在生物反应器中可靠地培养。该模型可用于评估抗体引导的化疗的疗效，并可能有助于预测临床反应。
