An imaging agent to detect androgen receptor and its active splice variants in prostate cancer
An imaging agent to detect androgen receptor and its active splice variants in prostate cancer
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DOI：
10.1172/jci.insight.87850
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发表时间：
2016-07-21
期刊：
影响因子：
8
通讯作者：
Sadar, Marianne D.
中科院分区：
文献类型：
--
作者：
Imamura, Yusuke;Tien, Amy H.;Sadar, Marianne D.
缺乏配体结合域（LBD）的雄激素受体（AR-V）的组成型活性剪接变体是转移性去势抵抗性前列腺癌（CRPC）对雄激素受体LBD靶向（AR LBD靶向）疗法的耐药机制。临床上存在强烈的未满足的需求，即识别具有 AR-V 阳性病变的前列腺癌患者，以确定他们是否会从进一步的 AR LBD 靶向治疗中受益，或者是否应该接受紫杉烷或 EPI-506 或 Galeterone 等研究药物。 EPI-506 (NCT02606123) 和 galeterone (NCT02438007) 均处于临床试验阶段，预计对 AR-V 阳性病变有效。 AR 激活函数 1 (AF-1) 是全长 AR 和 AR-V 的 N 端结构域所共有的。在这里，我们提供了开发直接结合 AR AF-1 以检测 AR-V 和全长 AR 的成像化合物的概念证明。 I-123-EPI-002 与 AR AF-1 具有特异性结合，这使得表达全长 AR 和 AR-V 的 CRPC 异种移植物能够直接可视化。我们的研究结果强调了 I-123-EPI-002 作为成像剂用于检测 CRPC 中全长 AR 和 AR-V 的潜力。
Constitutively active splice variants of androgen receptor (AR-Vs) lacking ligand-binding domain (LBD) are a mechanism of resistance to androgen receptor LBD-targeted (AR LBD-targeted) therapies for metastatic castration-resistant prostate cancer (CRPC). There is a strong unmet clinical need to identify prostate cancer patients with AR-V-positive lesions to determine whether they will benefit from further AR LBD-targeting therapies or should receive taxanes or investigational drugs like EPI-506 or galeterone. Both EPI-506 (NCT02606123) and galeterone (NCT02438007) are in clinical trials and are proposed to have efficacy against lesions that are positive for AR-Vs. AR activation function-1 (AF-1) is common to the N-terminal domains of full-length AR and AR-Vs. Here, we provide proof of concept for developing imaging compounds that directly bind AR AF-1 to detect both AR-Vs and full-length AR. I-123-EPI-002 had specific binding to AR AF-1, which enabled direct visualization of CRPC xenografts that express full-length AR and AR-Vs. Our findings highlight the potential of I-123-EPI-002 as an imaging agent for the detection of full-length AR and AR-Vs in CRPC.