Enhancing the efficacy of androgen signaling inhibitors in prostate cancer

增强雄激素信号抑制剂在前列腺癌中的功效

• 批准号: 10294787
• 负责人: XIAOQI LIU
• 金额: $ 46.73万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10294787
• 关键词: Acetates; Affect; Androgen Antagonists; Androgen Receptor; Androgens; Autocrine Communication; Biochemical; Bioinformatics; Cancer Patient; Castration; Cells; Clinic; Clinical; Coculture Techniques; Cultured Cells; Data; Development; Disease; Drug usage; Event; Fibroblasts; Fostering; Genetically Engineered Mouse; Goals; Health; Human; Investigation; Malignant Neoplasms; Malignant neoplasm of prostate; Methodology; Mission; Modeling; Molecular; Mus; Mutation; Neoplasm Circulating Cells; Neoplasm Metastasis; Organoids; Outcome; Paracrine Communication; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Play; Protein Family; Public Health; RNA analysis; Receptor Activation; Receptor Signaling; Research; Resistance; Resistance development; Role; Sampling; Signal Pathway; Signal Transduction; Specimen; System; Testing; Therapeutic; Tissue Microarray; United States National Institutes of Health; WNT Signaling Pathway; Withdrawal; Xenograft procedure; abiraterone; base; castration resistant prostate cancer; clinical translation; clinically relevant; docetaxel; gain of function; hormone therapy; improved; inhibitor/antagonist; innovation; loss of function; mouse model; new therapeutic target; novel; novel strategies; patient derived xenograft model; planar cell polarity; prostate cancer cell; prostate cancer progression; receptor; response; therapeutic target; transcriptome; transcriptome sequencing; tumor; tumor microenvironment

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.

标题：提高雄激素信号转导抑制剂治疗前列腺癌的疗效 摘要 已有文献证明，雄激素受体(AR)信号在去势中仍发挥关键作用。 耐药前列腺癌(CRPC)。事实上，雄激素信号抑制物(ASI)，如阿比特龙， 雄激素从头合成途径的抑制剂和直接的AR抑制剂苯扎鲁胺是主要药物 现已用于临床对CRPC的管理。不幸的是，基于ASI的治疗只改善了整体 患者存活时间延长了几个月。因此，了解ASI的潜在机制 提高基于ASI的治疗效果的新途径的抗药性和开发迫在眉睫 需要的。以识别其抑制可能克服ASI抗性的新途径/靶点为目标， 我们对rna-seq数据进行了广泛的生物信息学分析，包括来自配对前列腺的数据。 对苯扎鲁胺敏感性不同的癌细胞(PCa)，498个不同反应的PCa肿瘤 激素治疗组和52对PCa标本(肿瘤与癌旁正常对照)。-连环蛋白- 依赖的正则WNT级联和非依赖的非正则WNT信号是 被确定为其升高可能有助于获得ASI抵抗的途径。目标是 本研究的目的是明确Wnt信号在CRPC获得ASI抗性中的作用 并开发这些途径作为CRPC患者的新治疗靶点，这些患者对 阿希斯。中心假设是Wnt信号导致AR信号的结构性激活，从而 CRPC的进展与ASI耐药性的发展。这一假设将通过追求三个方面来检验 具体目的：(1)剖析-连环蛋白信号在前列腺癌对苯扎鲁胺耐药中的作用；(2) 研究非典型Wnt信号的激活如何促进苯扎鲁胺的耐药性 PCA；以及(3)测试同时抑制正则和非正则WNT级联是否 治疗苯扎鲁胺耐药PCa的有效途径及肿瘤意义的探讨 微环境Wnt在获得苯扎鲁胺耐药性中的作用。这些互补的目标将是 使用信号中间体的生化分析和使用功能增益和 通过可诱导的PCA小鼠模型、培养系统、人PCA异种移植、 和病人衍生的有机化合物方法学。这项研究的基本原理是，它将是第一个 综合探讨Wnt信号在CRPC获得ASI抗性中的重要性。这 贡献是重大的，因为它将(I)定义Wnt信号转导的分子机制 激活AR；(Ii)从遗传学角度评估这些通路如何促进前列腺癌的进展和转移； 以及(Iii)证明WNT级联反应是提高ASI疗效的关键治疗靶点。