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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：
10533763
负责人：
Andrew Caleb Hsieh
金额：
$ 42.53万
依托单位：
FRED HUTCHINSON CANCER 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/10533763
关键词：
Androgen Antagonists Androgen Receptor Androgens Binding Proteins Cancer Etiology Cancer Patient Cell Line Cell Proliferation Cell physiology Cessation of life Collection Communication DNA Data Development Disease Disease model Drug resistance Exhibits Experimental Genetics Gene Expression Process Gene Expression Regulation Generations Genes Genetic Models 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 Proliferating Protein Biosynthesis Proteins RNA Receptor Signaling Regulatory Element Role Sampling Seminal Series Signal Transduction Specificity Study models Testing Therapeutic Tissues Translation Initiation Translational Regulation Translations Treatment Efficacy United States Work abiraterone advanced prostate cancer androgen biosynthesis androgen deprivation therapy castration resistant prostate cancer cohort enzalutamide hormonal signals human model human tissue in vivo inhibitor intratumoral androgen mRNA Translation 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