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

基本信息

批准号：
10659141
负责人：
XIAOQI LIU
金额：
$ 48.52万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
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/10659141
关键词：
Acetates Affect Androgen Antagonists Androgen Receptor Androgens Autocrine Communication Biochemical Bioinformatics Cancer Patient Castration Cells Clinic Clinical Coculture Techniques Creativeness 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 Pharmacotherapy Play Protein Family Public Health RNA analysis Receptor Activation Receptor Signaling Research Resistance 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 castration resistant prostate cancer clinical translation clinically relevant docetaxel enzalutamide gain of function hormone therapy improved inhibitor inhibitor therapy innovation loss of function mouse model new therapeutic target novel novel strategies patient derived xenograft model pharmacologic planar cell polarity prostate cancer cell prostate cancer progression receptor response therapeutic target transcriptome transcriptome sequencing tumor tumor microenvironment

项目摘要

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：增强雄激素信号抑制剂在前列腺癌中的功效抽象的据记载，雄激素受体（AR）信号传导仍然在去势中发挥着关键作用。事实上，雄激素信号抑制剂（ASI），例如阿比特龙，是一种抗性前列腺癌（CRPC）的药物。雄激素从头合成途径抑制剂和直接AR抑制剂恩杂鲁胺是主要药物现在在临床上用于治疗 CRPC 不幸的是，基于 ASI 的治疗只能改善整体情况。因此，了解 ASI 的潜在机制。耐药性和开发新途径来提高基于 ASI 的疗法的功效迫在眉睫为了确定其抑制可能克服 ASI 耐药性的新途径/靶标，我们对 RNA-seq 数据进行了广泛的生物信息学分析，包括来自配对前列腺的数据对恩杂鲁胺具有不同敏感性的癌症 (PCa) 细胞，498 个具有不同反应的 PCa 肿瘤激素治疗和 52 对 PCa 标本（肿瘤与邻近正常细胞）。依赖的经典 Wnt 级联和 -连环蛋白独立的非经典 Wnt 信号传导被确定为其升高可能有助于获得 ASI 抗性的途径。拟议研究的目的是确定 Wnt 信号传导在 CRPC 获得 ASI 抵抗中的作用并利用这些途径作为对不再有反应的 CRPC 患者的新治疗靶点 ASI 的中心假设是 Wnt 信号传导导致 AR 信号传导的组成型激活，因此 CRPC 进展和 ASI 抵抗的发展将通过三个方面进行检验。具体目标 - (1) 剖析 β-连环蛋白信号在 PCa 恩杂鲁胺耐药中的作用 (2) 研究非经典 Wnt 信号传导的激活如何导致恩杂鲁胺耐药性 (3) 测试同时抑制经典和非经典 Wnt 级联是否是一种有效的方法治疗恩杂鲁胺耐药性 PCa 的有效方法并探讨肿瘤的意义获得恩杂鲁胺耐药性的微环境Wnt将是这些互补的目标。使用信号中间体的生化分析并采用功能获得和诱导性 PCa 小鼠模型、培养系统、人类 PCa 异种移植物的功能丧失策略，该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抵抗中的重要性。贡献意义重大，因为它将 (i) 定义 Wnt 信号传导的分子机制激活 AR；(ii) 从基因角度评估这些途径如何促进 PCa 进展和转移； (iii) 证明 Wnt 级联是增强 ASI 疗效的关键治疗靶点。