Characterization of an oxaliplatin sensitivity predictor in a preclinical murine model of colorectal cancer.
Characterization of an oxaliplatin sensitivity predictor in a preclinical murine model of colorectal cancer.
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DOI：
10.1158/1535-7163.mct-11-0937
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发表时间：
2012-07
影响因子：
5.7
通讯作者：
Hsu DS
中科院分区：
文献类型：
--
作者：
Kim MK;Osada T;Barry WT;Yang XY;Freedman JA;Tsamis KA;Datto M;Clary BM;Clay T;Morse MA;Febbo PG;Lyerly HK;Hsu DS
尽管当代化疗策略取得了进步，但转移性结直肠癌患者的长期生存仍然难以捉摸。为了改善临床结果，需要更好地了解药物敏感性的分子标记，以便与患者进行匹配治疗。在这项研究中，我们使用 NCI-60 细胞系的体外药物敏感性数据及其 Affymetrix 微阵列数据来开发基因表达特征来预测对奥沙利铂的敏感性。为了验证我们的奥沙利铂敏感性特征，在来自切除的人类结直肠肿瘤的 NOD-SCID 小鼠中开发了患者来源的结直肠癌外植体 (PDCCE)。基因表达谱分析发现 PDCCE 与其亲代人类肿瘤之间存在相似性，表明它们可用于研究体内药物敏感性。然后使用奥沙利铂治疗的 14 个 PDCCE 的反应数据在体内验证奥沙利铂敏感性特征，结果发现准确性为 92.9%（敏感性 = 87.5%；特异性 = 100%）。我们的研究结果表明，PDCCE 可以成为研究结直肠癌药物敏感性的新来源。此外，基于基因组的分析有可能被纳入未来的策略中，以优化转移性结直肠癌患者的个体化治疗。
Despite advances in contemporary chemotherapeutic strategies, long term survival still remains elusive for patients with metastatic colorectal cancer. A better understanding of the molecular markers of drug sensitivity to match therapy with patient is needed to improve clinical outcomes. In this study, we used in vitro drug sensitivity data from the NCI-60 cell lines together with their Affymetrix microarray data to develop a gene expression signature to predict sensitivity to oxaliplatin. In order to validate our oxaliplatin sensitivity signature, Patient-Derived Colorectal Cancer Explants (PDCCEs) were developed in NOD-SCID mice from resected human colorectal tumors. Analysis of gene expression profiles found similarities between the PDCCEs and their parental human tumors, suggesting their utility to study drug sensitivity in vivo. The oxaliplatin sensitivity signature was then validated in vivo with response data from 14 PDCCEs treated with oxaliplatin and was found to have an accuracy of 92.9% (Sensitivity=87.5%; Specificity=100%). Our findings suggest that PDCCEs can be a novel source to study drug sensitivity in colorectal cancer. Furthermore, genomic-based analysis has the potential to be incorporated into future strategies to optimize individual therapy for patients with metastatic colorectal cancer.