Tumor Tissue Explant Culture of Patient-Derived Xenograft as Potential Prioritization Tool for Targeted Therapy
Tumor Tissue Explant Culture of Patient-Derived Xenograft as Potential Prioritization Tool for Targeted Therapy
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DOI：
10.3389/fonc.2019.00017
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发表时间：
2019-01-22
影响因子：
4.7
通讯作者：
Porgador, Angel
中科院分区：
文献类型：
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作者：
Ghosh, Susmita;Prasad, Manu;Porgador, Angel
尽管头颈癌（HNC）治疗取得了显着进展，但这种转移性疾病的生存率仍然很低。为患者量身定制合适的治疗方法是一项重大挑战，并且凸显了对能够预测临床反应的良好临床前模型的需求尚未得到满足。因此，我们开发了一种准确且省时的肿瘤离体分析（TEVA）系统药物筛选方法，可以预测患者特异性药物反应。在这项研究中，我们生成了 6 个患者来源的异种移植物 (PDX)，用于 TEVA。简而言之，将PDX切成2 x 2 x 2 mm(3)的外植体并用临床相关药物处理24小时。通过免疫组织化学评估肿瘤细胞增殖和死亡并计算TEVA评分。对四种 PDX 和三种药物并排进行了体外和体内药效研究，以探索 TEVA 和 PDX 体内治疗之间的相关性。还探讨了药物组合的功效。培养时间的优化规定 24 小时是检测药物反应和药物渗透 2 x 2 x 2 mm(3) 外植体的时间范围，因为信号通路显着改变。 TEVA 中的肿瘤对药物的反应与小鼠中的药物功效显着对应。总体而言，这种低成本、稳健、相对简单且高效的基于 3D 组织的方法，采用来自一种 PDX 的材料，可以绕过在免疫缺陷的 PDX 小鼠中进行药物验证的必要性。当提出多个靶点时，我们的数据为利用 TEVA 预测肿瘤对靶向治疗和化疗的反应提供了潜在的理由。
Despite of remarkable progress made in the head and neck cancer (HNC) therapy, the survival rate of this metastatic disease remain low. Tailoring the appropriate therapy to patients is a major challenge and highlights the unmet need to have a good preclinical model that will predict clinical response. Hence, we developed an accurate and time efficient drug screening method of tumor ex vivo analysis (TEVA) system, which can predict patient-specific drug responses. In this study, we generated six patient derived xenografts (PDXs) which were utilized for TEVA. Briefly, PDXs were cut into 2 x 2 x 2 mm(3) explants and treated with clinically relevant drugs for 24 h. Tumor cell proliferation and death were evaluated by immunohistochemistry and TEVA score was calculated. Ex vivo and in vivo drug efficacy studies were performed on four PDXs and three drugs side-by-side to explore correlation between TEVA and PDX treatment in vivo. Efficacy of drug combinations was also ventured. Optimization of the culture timings dictated 24 h to be the time frame to detect drug responses and drug penetrates 2 x 2 x 2 mm(3) explants as signaling pathways were significantly altered. Tumor responses to drugs in TEVA, significantly corresponds with the drug efficacy in mice. Overall, this low cost, robust, relatively simple and efficient 3D tissue-based method, employing material from one PDX, can bypass the necessity of drug validation in immune-incompetent PDX-bearing mice. Our data provides a potential rationale for utilizing TEVA to predict tumor response to targeted and chemo therapies when multiple targets are proposed.