Enhancing the efficacy of androgen signaling inhibitors in prostate cancer

标题：增强雄激素信号传导抑制剂在前列腺癌中的疗效 摘要 据记载，雄激素受体（AR）信号传导仍然在去势中发挥关键作用- 耐药前列腺癌（CRPC）。事实上，雄激素信号传导抑制剂（ASI），如阿比特龙， 从头雄激素合成途径抑制剂和直接AR抑制剂恩杂鲁胺是主要药物 目前临床上用于治疗CRPC。不幸的是，基于ASI的治疗只能改善整体 患者存活数月。因此，了解ASI的潜在机制 迫切需要开发新的途径来提高基于ASI的治疗的疗效， needed.为了鉴定其抑制可能克服ASI抗性的新途径/靶标， 我们对RNA-seq数据进行了广泛的生物信息学分析， 对Enzalutamide具有不同敏感性的癌（PCa）细胞，498例具有不同应答的PCa肿瘤 52对PCa标本（肿瘤与癌旁正常组织）。β-连环蛋白- 依赖的经典Wnt级联反应和β-连环蛋白非依赖的非经典Wnt信号传导是 被鉴定为其升高可能有助于获得ASI抗性的途径。客观 这项研究的目的是确定Wnt信号在CRPC获得ASI抗性中的作用 并利用这些途径作为CRPC患者的新治疗靶点， 人工智能中心假设是Wnt信号传导引起AR信号传导的组成性激活，因此 CRPC进展和ASI耐药性的发展。这一假设将通过以下三个方面来检验： 具体目的-（1）分析β-连环蛋白信号传导在PCa的恩杂鲁胺抗性中的作用;（2）分析β-连环蛋白信号传导在PCa的恩杂鲁胺抗性中的作用。 研究非经典Wnt信号传导的激活如何导致Enzalutamide耐药， PCa;和（3）测试同时抑制典型和非典型Wnt级联是否是一种有效的方法。 Enzalutamide耐药前列腺癌治疗的有效途径及肿瘤意义的探讨 微环境Wnt在获得恩杂鲁胺耐药性中的作用。这些相辅相成的目标将是 使用信号传导中间体的生化分析和采用功能获得来完成， 用诱导型PCa小鼠模型、培养系统、人PCa异种移植物、 和患者来源的类器官方法学。这项研究的基本原理是，它将是第一个 全面探讨Wnt信号在CRPC获得ASI抗性中的重要性。这 贡献是重要的，因为它将（i）定义Wnt信号传导的分子机制， （ii）从遗传学上评估这些途径如何促进PCa进展和转移; 和（iii）证明Wnt级联作为关键的治疗靶点以增强ASI的功效。

Title: Enhancing the efficacy of androgen signaling inhibitors in prostate cancer Abstract It has been documented that androgen receptor (AR) signaling remains to play a critical role in castration- resistant prostate cancer (CRPC). Indeed, Androgen Signaling Inhibitors (ASI), such as abiraterone, an inhibitor of de novo androgen synthesis pathway, and enzalutamide, a direct AR inhibitor, are major drugs used in clinic to manage CRPC now. Unfortunately, ASI-based treatment only improves the overall patient survival by several months. Therefore, understanding the underlying mechanisms of ASI resistance and development of novel avenues to increase the efficacy of ASI-based therapy are urgently needed. With the goal to identify new pathways/targets whose inhibition might overcome ASI resistance, we performed extensive bioinformatics analyses of RNA-seq data including those from paired prostate cancer (PCa) cells with different sensitivities to enzalutamide, 498 PCa tumors with different responses to hormone therapy and 52 pairs of PCa specimen (tumors vs adjacent normal). Both the -catenin- dependent canonical Wnt cascade and the -catenin-independent non-canonical Wnt signaling were identified as pathways whose elevation might contribute to acquisition of ASI resistance. The objective of the proposed research is to define the roles of Wnt signaling in acquisition of ASI resistance in CRPC and to exploit these pathways as novel therapeutic targets for CRPC patients who no longer respond to ASIs. The central hypothesis is that Wnt signaling causes constitutive activation of AR signaling, thus CRPC progression and development of ASI resistance. This hypothesis will be tested by pursuing three Specific Aims - (1) to dissect the role of-catenin signaling in enzalutamide resistance of PCa; (2) to examine how activation of the non-canonical Wnt signaling contributes to enzalutamide resistance in PCa; and (3) to test whether simultaneous inhibition of canonical and non-canonical Wnt cascades is an effective approach to treat enzalutamide-resistant PCa and to probe the significance of tumor microenvironment Wnt in the acquisition of enzalutamide resistance. These complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing gain-of-function and loss-of-function strategies with inducible PCa mouse models, culture systems, human PCa xenograft, and patient-derived organoid methodologies. The rationale for the research is that it will be the first to comprenhensively probe the importance of Wnt signaling in acquisition of ASI resistance of CRPC. This contribution is significant because it will (i) define the molecular mechanism by which Wnt signaling activates AR; (ii) genetically evaluate how these pathways contribute to PCa progression and metastasis; and (iii) demonstrate Wnt cascades as critical therapeutic targets to enhance the efficacy of ASI.