Temozolomide in the Era of Precision Medicine.
Temozolomide in the Era of Precision Medicine.
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DOI：
10.1158/0008-5472.can-16-2983
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发表时间：
2017-02-15
期刊：
影响因子：
11.2
通讯作者：
Pommier Y
中科院分区：
文献类型：
--
作者：
Thomas A;Tanaka M;Trepel J;Reinhold WC;Rajapakse VN;Pommier Y
在这一期的《癌症研究》中，Nagel和他的同事们证明了测定癌症DNA修复能力的检测方法在预测替莫唑胺反应中的价值。利用基于荧光的多重流式细胞术宿主细胞再激活（FM-HCR）试验，同时读出多种途径的DNA修复能力，他们表明，来自细胞系数据的多变量药物反应模型适用于胶质母细胞瘤患者来源的异种移植（PDX）模型。在这篇评论中，我们首先概述了替莫唑胺的作用机制和目前的临床应用，到目前为止，替莫唑胺主要局限于胶质母细胞瘤。鉴于临床应用功能分析的挑战，我们认为功能读数是由基因组特征近似。在这种情况下，肿瘤的MGMT活性和MMR状态的结合是决定替莫唑胺敏感性的重要参数。需要更可靠的方法来确定MGMT活性，因为DNA甲基化，目前的标准并不能准确反映MGMT的表达。此外，MMR的基因组学也得到了保证。此外，基于MGMT在不同实体肿瘤中的表达模式，基于我们目前对替莫唑胺活性分子基础的理解，我们提出了在更广泛的癌症中重新审视替莫唑胺使用的案例。
In this issue of Cancer Research, Nagel and colleagues demonstrate the value of assays that determine the DNA repair capacity of cancers in predicting response to temozolomide. Using a fluorescence-based multiplex flow-cytometric host cell reactivation (FM-HCR) assay that provides simultaneous readout of DNA repair capacity across multiple pathways, they show that the multivariate drug response models derived from cell line data were applicable to patient derived xenograft (PDX) models of glioblastoma. In this commentary, we first outline the mechanism of activity and current clinical application of temozolomide, which, until now has been largely limited to glioblastoma. Given the challenges of clinical application of functional assays, we argue that functional readouts be approximated by genomic signatures. In this context, a combination of MGMT activity and MMR status of the tumor are important parameters that determine sensitivity to temozolomide. More reliable methods are needed to determine MGMT activity as DNA methylation, the current standard does not accurately reflect the expression of MGMT. Also genomics for MMR are warranted. Further, based on patterns of MGMT expression across different solid tumors, we make a case for revisiting temozolomide use in a broader spectrum of cancers based on our current understanding of its molecular basis of activity.