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：
10062493
负责人：
Andrew Caleb Hsieh
金额：
$ 42.07万
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 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062493
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 experimental study hormonal signals human model human tissue in vivo inhibitor/antagonist 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.

抽象的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引起人们的关注。不幸的医源性效应助长了患者新的致命性前列腺癌表型。特别是，非神经内分泌雄激素受体低去势抵抗性前列腺癌 (CRPC)，这是一种侵袭性形式这种疾病在患者中的发病率正在增加，并且都是致命的。主要障碍治疗的进展在于缺乏相关的疾病模型以及对疾病的了解非常少产生这种表型的机制。蛋白质合成的过程很早就被认为服从于癌症病因学中 DNA 和 RNA 水平的改变。然而，我们实验室的工作和其他人揭示蛋白质合成控制是一个动态过程，不仅协调体积 mRNA 翻译，以及对癌症表型很重要的不同 mRNA 的专门翻译。最近，我们的实验室开发并表征了一种新的人类和体内体外工具包。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转导和 mRNA 翻译起始过程，这对于雄激素受体低水平至关重要 CRPC 增长。我们假设雄激素受体低的 CRPC 是由不同的 mRNA 网络，从而导致持续的肿瘤生长，这可能代表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的异种移植物以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且新出现的疾病过程中的合成控制。要做的事因此，我们将致力于以下目标：1）确定雄激素受体的作用机制与翻译装置通信，2）描述异常蛋白质合成如何驱动翻译不同的致癌 mRNA，以及 3) 阐明靶向翻译起始的治疗功效雄激素受体低 CRPC。最终，这些研究有望揭示雄激素受体低水平基因调控的新范式前列腺癌，并为靶向蛋白质合成装置提供临床前基础越来越常见的高度侵袭性疾病。