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：提高前列腺癌中雄激素信号抑制剂的效率抽象的已经有记录，雄激素受体（AR）信号传导在cast割中仍然起着至关重要的作用。抗性前列腺癌（CRPC）。实际上，雄激素信号抑制剂（ASI），例如阿比罗酮，从头雄激素合成途径的抑制剂，直接AR抑制剂enzalutamide是主要药物现在在诊所中用于管理CRPC。不幸的是，基于ASI的治疗只能改善整体患者生存几个月。因此，了解ASI的潜在机制紧急的抗药性和发展途径提高基于ASI的治疗的效率是迫切的需要。以确定抑制可能克服ASI抵抗的新途径/目标的目标，我们对RNA-seq数据进行了广泛的生物信息学分析，包括配对前列腺的数据癌症（PCA）细胞对enzalutamide的敏感性不同，498个PCA肿瘤具有不同的反应进行骑马疗法和52对PCA标本（肿瘤与相邻正常）。两者都是-catenin- 依赖的规范Wnt级联和-catenin独立的非经典Wnt信号是被确定为途径，其升高可能有助于获得ASI抗性。目标拟议的研究是定义Wnt信号在获得CRPC中ASI抗性中的作用并利用这些途径作为不再反应的CRPC患者的新型治疗靶标 ASIS。中心假设是Wnt信号导致AR信号的组成型激活，因此 CRPC的进展和ASI抗性的发展。该假设将通过追求三个具体目的 - （1）剖析 -catenin信号传导在PCA的enzalutamide抗性中的作用；（2）至检查非经典Wnt信号的激活如何有助于enzalutamide抗性 PCA; （3）测试同时抑制规范和非典型的wnt级联有效治疗耐烯氨酰胺的PCA的有效方法并探测肿瘤的重要性微环境Wnt在获得enzalutamide耐药性中。这些完整的目标将是使用信号中间体的生化分析并采用功能奖励和具有诱导PCA小鼠模型，培养系统，人PCA谱的功能丧失策略，和患者衍生的器官方法。研究的理由是，它将是第一个全面探讨WNT信号在获得CRPC的ASI抗性中的重要性。这贡献很重要，因为它将（i）定义Wnt信号传导的分子机制激活AR；（ii）一般评估这些途径如何促进PCA进展和转移；（iii）将Wnt级联反应作为关键的治疗靶标，以提高ASI的效率。