Table_1_Molecular Phenotyping of AR Signaling for Predicting Targeted Therapy in Castration Resistant Prostate Cancer.docx

Castration-resistant prostate cancer (CRPC) is defined by resistance of the tumor to androgen deprivation therapy (ADT). Several molecular changes, particularly in the AR signaling cascade, have been described that may explain ADT resistance. The variety of changes may also explain why the response to novel therapies varies between patients. Testing the specific molecular changes may be a major step towards personalized treatment of CRPC patients. The aim of our study was to evaluate the molecular changes in the AR signaling cascade in CRPC patients. We have developed and validated several methods which are easy to use, and require little tissue material, for exploring AR signaling pathway changes simultaneously. We found that the AR signaling pathway is still active in the majority of our CRPC patients, due to molecular changes in AR signaling components. There was heterogeneity in the molecular changes observed, but we could classify the patients into 4 major subgroups which are: AR mutation, AR amplification, active intratumoral steroidogenesis, and combination of AR amplification and active intratumoral steroidogenesis. We suggest characterizing the AR signaling pathway in CRPC patients before beginning any new treatment, and a recent fresh tissue sample from the prostate or a metastatic site should be obtained for the purpose of this characterization.

去势抵抗性前列腺癌（Castration-resistant prostate cancer, CRPC）被定义为肿瘤对雄激素剥夺治疗（Androgen Deprivation Therapy, ADT）产生耐药性的疾病状态。目前已报道多种分子改变，尤其是雄激素受体（Androgen Receptor, AR）信号级联反应中的分子改变，可用于阐释ADT耐药的发生机制；而这类分子改变的多样性，同样可解释不同患者对新型治疗方案的响应存在差异的原因。检测此类特异性分子改变，或是推动CRPC患者实现个性化治疗的重要环节。本研究旨在评估CRPC患者体内AR信号级联反应的分子改变情况。我们开发并验证了多种操作简便、所需组织样本量极少的检测方法，可同时完成AR信号通路相关改变的筛查。研究结果显示，受AR信号通路组分的分子改变影响，本研究纳入的多数CRPC患者体内AR信号通路仍处于激活状态。尽管观察到的分子改变存在异质性，但我们可将受试者划分为4个主要亚组：AR突变、AR扩增、肿瘤内类固醇生成活跃，以及AR扩增与肿瘤内类固醇生成活跃共存型。我们建议，在为CRPC患者启动任何新的治疗方案前，均应先对其AR信号通路进行特征分型，并需获取取自前列腺或转移灶的新鲜组织样本以完成该分型工作。