A growth model of neuroendocrine tumor surrogates and the efficacy of a novel somatostatin-receptor-guided antibody-drug conjugate: Perspectives on clinical response?
A growth model of neuroendocrine tumor surrogates and the efficacy of a novel somatostatin-receptor-guided antibody-drug conjugate: Perspectives on clinical response?
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DOI：
10.1016/j.surg.2019.04.073
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发表时间：
2020-01
期刊：
影响因子：
3.8
通讯作者：
Jaskula-Sztul R
中科院分区：
文献类型：
--
作者：
Herring B;Whitt J;Aweda T;Ou J;Guenter R;Lapi S;Berry J;Chen H;Liu X;Rose JB;Jaskula-Sztul R
由于缺乏用于测试个性化治疗的患者来源的异种移植物（PDX）和神经内分泌肿瘤（NET）的其他临床前模型，我们开发了灌注的3D生物反应器模型以从患者来源的NET培养肿瘤替代物。这项工作评估了替代培养的持续时间和替代对新型抗体-药物缀合物（ADC）的反应。培养了27个患者来源的NET。在肿瘤植入两个生物反应器之前，评估胰腺NET（pNET）异种移植物（BON-1）肿瘤的组织切片的SSTR 2表达。一种替代物用ADC处理，所述ADC包含与生长抑素受体2（SSTR 2）抗体连接的抗有丝分裂单甲基奥瑞他汀-E（MMAE）。通过用IR-783和RealTime-Glo™ AnnexinV凋亡和坏死测定（Promega）预成像孵育六天来评估活力和治疗反应。同样评价了原代人pNET。平均替代生长持续时间为34.8天。与对照相比，经处理的BON-1替代物表现出较少的增殖（1.2与1.9倍）和较高的凋亡（1.5与1.1倍），而经处理的患者来源的NET生物反应器表现出较高程度的凋亡（13与9倍）和坏死（2.5与1.6倍）。患者来源的NET替代物可以在生物反应器内可靠地培养。该模型可用于体外评价抗体引导化疗的疗效，并可用于预测临床反应。
As patient-derived xenografts (PDXs) and other preclinical models of neuroendocrine tumors (NETs) for testing personalized therapeutics are lacking, we have developed a perfused 3D bioreactor model to culture tumor surrogates from patient-derived NETs. This work evaluates the duration of surrogate culture and surrogate response to a novel antibody-drug conjugate (ADC). 27 Patient-derived NETs were cultured. Histologic sections of a pancreatic NET (pNET) xenograft (BON-1) tumor were assessed for SSTR2 expression before tumor implantation into two bioreactors. One surrogate was treated with ADC comprised an anti-mitotic Monomethyl auristatin-E (MMAE), linked to a somatostatin receptor 2 (SSTR2) antibody. Viability and therapeutic response were assessed by pre-imaging incubation with IR-783 and the RealTime-Glo™ AnnexinV Apoptosis and Necrosis Assay (Promega) over six days. A primary human pNET was likewise evaluated. Mean surrogate growth duration was 34.8 days. Treated BON-1 surrogates exhibited less proliferation (1.2 vs. 1.9-fold) and higher apoptosis (1.5 vs. 1.1-fold) than controls, while treated patient-derived NET bioreactors exhibited higher degrees of apoptosis (13 vs. 9-fold) and necrosis (2.5 vs. 1.6-fold). Patient-derived NET surrogates can be reliably cultured 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.
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影响因子：
4.3
作者：
Kawasaki K;Fujii M;Sato T
通讯作者：
Sato T
影响因子：
8.8
作者：
Vijayvergia N;Boland PM;Handorf E;Gustafson KS;Gong Y;Cooper HS;Sheriff F;Astsaturov I;Cohen SJ;Engstrom PF
通讯作者：
Engstrom PF
影响因子：
28.4
作者：
Dasari, Arvind;Shen, Chan;Yao, James C.
通讯作者：
Yao, James C.
影响因子：
10.9
作者：
D'Amico, Lucia;Menzel, Ulrike;Zippelius, Alfred
通讯作者：
Zippelius, Alfred
影响因子：
4.1
作者：
Pavel, M.;O'Toole, D.;Oberg, K.
通讯作者：
Oberg, K.