A Radiotracer Strategy to Quantify PARP-1 Expression In Vivo Provides a Biomarker That Can Enable Patient Selection for PARP Inhibitor Therapy.
A Radiotracer Strategy to Quantify PARP-1 Expression In Vivo Provides a Biomarker That Can Enable Patient Selection for PARP Inhibitor Therapy.
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DOI：
10.1158/0008-5472.can-16-0416
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发表时间：
2016-08-01
期刊：
影响因子：
11.2
通讯作者：
Mach RH
中科院分区：
文献类型：
--
作者：
Makvandi M;Xu K;Lieberman BP;Anderson RC;Effron SS;Winters HD;Zeng C;McDonald ES;Pryma DA;Greenberg RA;Mach RH
尽管PARP抑制剂可用于癌症治疗，但仍然缺乏一种生物标志物来明确区分患者以选择这种治疗方法。在这里，我们描述了一种基于放射性示踪剂的方法来解决这个问题，使用新型化合物[125I]KX1作为PARP-1选择性放射性示踪剂，可以准确测量PARP-1在体外和体内的表达。PARP放射性示踪剂[125I]KX1的药理学特性在多个细胞系中得到表征，其中单药敏感性与[125I]KX1与PARP-1的结合相关。[125I]KX1的体内评价验证了体外结果，验证了PARP放射性示踪剂将PARP-1酶表达定义为体内生物标志物。值得注意的是，用[125I]KX1量化的PARP-1表达与用PARP抑制剂评估的细胞系的细胞毒敏感性呈正相关。总的来说，我们的研究结果定义了一种新的技术，它有可能作为一种辅助诊断来识别最有可能对PARP抑制剂有治疗反应的患者。
Despite the availability of PARP inhibitors for cancer therapy, a biomarker to clearly stratify patients for selection of this treatment remains lacking. Here we describe a radiotracer-based method that addresses this issue, using the novel compound [125I]KX1 as a PARP-1–selective radiotracer that can accurately measure PARP-1 expression in vitro and in vivo. The pharmacologic properties of the PARP radiotracer [125I]KX1 was characterized in multiple cell lines where single-agent sensitivity was correlated with [125I]KX1 binding to PARP-1. In vivo evaluation of [125I]KX1 verified in vitro results, validating PARP radiotracers to define PARP-1 enzyme expression as an in vivo biomarker. Notably, PARP-1 expression as quantified by [125I]KX1 correlated positively with the cytotoxic sensitivity of cell lines evaluated with PARP inhibitors. Overall, our results defined a novel technology with the potential to serve as a companion diagnostic to identify patients most likely to respond therapeutically to a PARP inhibitor.