Vancouver Prostate Centre, Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.
Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.
Eur Urol. 2018 Jun;73(6):949-960. doi: 10.1016/j.eururo.2018.02.019. Epub 2018 Mar 12.
Although androgen deprivation therapy is initially effective in controlling growth of hormone-naive prostate cancers (HNPCs) in patients, currently incurable castration-resistant prostate cancer (CRPC) inevitably develops.
To identify CRPC driver genes that may provide new targets to enhance CRPC therapy.
DESIGN, SETTING, AND PARTICIPANTS: Patient-derived xenografts (PDXs) of HNPCs that develop CRPC following host castration were examined for changes in expression of genes at various time points after castration using transcriptome profiling analysis; particular attention was given to pre-CRPC changes in expression indicative of genes acting as potential CRPC drivers.
The functionality of a potential CRPC driver was validated via its knockdown in cultured prostate cancer cells; its clinical relevance was established using data from prostate cancer patient databases.
Eighty genes were found to be significantly upregulated at the CRPC stage, while seven of them also showed elevated expression prior to CRPC development. Among the latter, growth factor receptor bound protein 10 (GRB10) was the most significantly and consistently upregulated gene. Moreover, elevated GRB10 expression in clinical prostate cancer samples correlated with more aggressive tumor types and poorer patient treatment outcome. GRB10 knockdown markedly reduced prostate cancer cell proliferation and activity of AKT, a well-established CRPC mediator. A positive correlation between AKT activity and GRB10 expression was also found in clinical cohorts.
GRB10 acts as a driver of CRPC and sensitizes androgen receptor pathway inhibitors, and hence GRB10 targeting provides a novel therapeutic strategy for the disease.
Development of castration-resistant prostate cancer (CRPC) is a major problem in the management of the disease. Using state-of-the-art patient-derived hormone-naive prostate cancer xenograft models, we found and validated the growth factor receptor bound protein 10 gene as a driver of CRPC, indicating that it may be used as a new molecular target to enhance current CRPC therapy.
尽管雄激素剥夺疗法最初能有效控制激素敏感型前列腺癌（HNPCs）患者的肿瘤生长，但不可避免地会发展为目前无法治愈的去势抵抗性前列腺癌（CRPC）。
确定可能为增强 CRPC 治疗提供新靶点的 CRPC 驱动基因。
设计、地点和参与者：使用转录组谱分析检查接受去势的 HNPC 衍生的异种移植物（PDX）在去势后各个时间点的基因表达变化，特别关注预示潜在 CRPC 驱动基因的表达变化；使用前列腺癌患者数据库中的数据来验证潜在 CRPC 驱动基因的功能，并建立其临床相关性。
在 CRPC 阶段发现有 80 个基因显著上调，其中 7 个基因在 CRPC 发生前也表现出升高的表达。在后者中，生长因子受体结合蛋白 10（GRB10）是上调最显著和一致的基因。此外，临床前列腺癌样本中 GRB10 表达的升高与更具侵袭性的肿瘤类型和较差的患者治疗结果相关。GRB10 敲低显著降低了前列腺癌细胞的增殖和 AKT 的活性，AKT 是一种公认的 CRPC 介质。在临床队列中也发现了 AKT 活性与 GRB10 表达之间的正相关。
GRB10 作为 CRPC 的驱动基因，并敏化雄激素受体通路抑制剂，因此针对 GRB10 提供了一种治疗该疾病的新策略。
去势抵抗性前列腺癌（CRPC）的发展是该疾病管理的主要问题。使用最先进的患者源性去势敏感型前列腺癌异种移植模型，我们发现并验证了生长因子受体结合蛋白 10 基因作为 CRPC 的驱动基因，表明它可能被用作增强现有 CRPC 治疗的新分子靶点。
