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Hormone signaling and translation control in advanced prostate cancer

晚期前列腺癌的激素信号传导和翻译控制

基本信息

批准号：
10311029
负责人：
Andrew Caleb Hsieh
金额：
$ 16.4万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-06 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10311029
关键词：
Address Androgen Antagonists Androgen Receptor Androgens Binding Proteins Cancer Etiology Cancer Patient Cell Line Cell Proliferation Cell physiology Cessation of life Collection DNA Data Development Disease Disease model Drug resistance Exhibits Gene Expression Process Gene Expression Regulation Generations Genes Genetic Genetic Models Genetic Translation Goals Growth Human Hyperactivity Iatrogenesis In Vitro Individual International Laboratories Link Maintenance Malignant Neoplasms Malignant neoplasm of prostate Measures Mediating Messenger RNA Methods Modeling Molecular Mus Neurosecretory Systems Oncogenes Oncogenic Organoids Pathogenesis Patients Peptide Initiation Factors Phenotype Process Protein Biosynthesis Proteins RNA Receptor Signaling Regulation Regulatory Element Role Sampling Seminal Series Signal Transduction Specificity Study models Testing Therapeutic Tissues Translation Initiation Translations Treatment Efficacy United States Work abiraterone advanced prostate cancer androgen biosynthesis androgen deprivation therapy castration resistant prostate cancer cohort enzalutamide experimental study hormonal signals human model human tissue in vivo inhibitor intratumoral androgen men mouse model new technology patient derived xenograft model pre-clinical preclinical study prognostic programs prostate cancer cell receptor response ribosome profiling therapy development transcriptome treatment response tumor growth

项目摘要

ABSTRACT The recent advent of highly potent inhibitors of the androgen receptor and androgen biosynthesis has had the unfortunate iatrogenic effect of fueling new lethal prostate cancer phenotypes in patients. In particular, non- neuroendocrine androgen receptor-low castration resistant prostate cancer (CRPC), an aggressive form of this disease, is increasing in occurrence amongst patients and is uniformly fatal. The main barriers against therapeutic advances are a paucity of relevant disease models and a very poor understanding of the mechanisms that give rise to this phenotype. The process of protein synthesis has long been considered subordinate to alterations at the levels of DNA and RNA in cancer etiology. However, work from our laboratory and others have revealed that protein synthesis control is a dynamic process that coordinates not only bulk mRNA translation, but also the specialized translation of distinct mRNAs important for cancer phenotypes. Recently, our laboratory has developed and characterized a new in vitro and in vivo toolkit of both human and murine androgen receptor-low CRPC. We have used these models to discover a critical link between androgen receptor signaling and the process of mRNA translation initiation, which is critical for androgen receptor-low CRPC growth. We hypothesize that androgen receptor-low CRPC is driven by the specific translation of distinct mRNA networks, thereby leading to persistent tumor growth, which may represent a therapeutic vulnerability. Our long-term objective is to utilize state-of-the-art mouse models, ribosome profiling, and patient derived xenografts to definitively investigate the fundamental link between the androgen receptor and protein synthesis control in a highly relevant and newly emerging disease course for prostate cancer patients. To do so, we will address the following aims: 1) determine the mechanism by which the androgen receptor communicates with the translation apparatus, 2) delineate how aberrant protein synthesis drives the translation of distinct oncogenic mRNAs, and 3) elucidate the therapeutic efficacy of targeting translation initiation in androgen receptor-low CRPC. Ultimately, these studies are poised to uncover a new paradigm for gene regulation in androgen receptor-low prostate cancer and provide the preclinical basis for targeting the protein synthesis apparatus in an increasingly common highly aggressive disease.

摘要最近出现的雄激素受体和雄激素生物合成的高效抑制剂已经在患者中助长新的致命前列腺癌表型的医源性不幸效应。特别是，非- 神经内分泌雄激素受体-低抗去势前列腺癌(CRPC)，一种侵袭性形式这种疾病在患者中的发病率正在增加，而且通常是致命的。主要的障碍是治疗方面的进展缺乏相关的疾病模型，而且对产生这种表型的机制。长期以来，人们一直认为蛋白质的合成过程在癌症病因学中，从属于DNA和RNA水平的变化。然而，我们实验室的工作而其他人则揭示了蛋白质合成控制是一个动态的过程，它不仅协调大量的蛋白质信使核糖核酸翻译，也是对癌症表型重要的不同信使核糖核酸的专门翻译。最近，我们实验室开发并表征了一种新的人和动物体内和体外工具包小鼠雄激素受体-低CRPC。我们使用这些模型来发现雄激素之间的关键联系受体信号和mRNA翻译起始过程对雄激素受体低水平起关键作用 CRPC增长。我们假设雄激素受体低CRPC是由雄激素受体低CRPC的特异性翻译所驱动的。不同的mRNA网络，从而导致肿瘤的持续生长，这可能是一种治疗方法脆弱性。我们的长期目标是利用最先进的小鼠模型、核糖体分析和患者衍生异种移植明确研究雄激素受体和蛋白质之间的基本联系前列腺癌患者高度相关和新出现的病程中的综合控制。去做因此，我们将解决以下目标：1)确定雄激素受体与翻译设备通信，2)描述异常蛋白质合成如何驱动翻译以及3)阐明靶向翻译起始在肿瘤中的治疗效果。雄激素受体-低CRPC。最终，这些研究将揭开雄激素受体基因调控的新范式--低水平为靶向蛋白质合成装置治疗前列腺癌提供了临床前基础越来越常见的高度侵袭性疾病。