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：
10175894
负责人：
Andrew Caleb Hsieh
金额：
$ 16.67万
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/10175894
关键词：
Address Anabolism Androgen Antagonists Androgen Receptor Androgens Cancer Cell Growth Cancer Etiology Cancer Patient Castration Cell Maintenance Cells Complex DNA Disease Disease model Drug Targeting Drug resistance Epigenetic Process Estrogen receptor positive Eukaryotic Initiation Factor-4F Evaluation Gene Expression Regulation Genes Genetic Information Processing Pathway Genetic Models Genetic Translation Genotoxic Stress Goals Growth Guanine Hormone Antagonists Hormone Responsive Hormones Human Iatrogenesis Incidence Laboratories Lead Link Malignant Neoplasms Malignant neoplasm of prostate Measures Mediating Memorial Sloan-Kettering Cancer Center Messenger RNA Modeling Modification Molecular Nuclear Nuclear Hormone Receptors Organoids Pathway interactions Patients Pharmaceutical Preparations Phenotype Process Protein Biosynthesis Protein Deregulation RNA Receptor Inhibition Receptor Signaling Regulatory Element Research Resistance Resources Role Signal Pathway Specimen Stress Testing Therapeutic Translating Translation Initiation Translational Research Translations Work abiraterone advanced prostate cancer base biological adaptation to stress cancer cell cancer therapy cancer type castration resistant prostate cancer clinically relevant design hormonal signals hormone resistance improved inhibitor/antagonist interest malignant breast neoplasm mouse model next generation novel therapeutic intervention novel therapeutics pre-clinical prostate cancer cell prostate cancer model prostate cancer progression resistance mechanism response ribosome profiling synergism therapeutic evaluation therapeutic target therapy resistant translational medicine tumor growth tumor progression tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY/ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 20-014. 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, castration resistant prostate cancer (CRPC) that is resistant to therapies such as enzalutamide and abiraterone are 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 uncovered a new functional link between androgen receptor signaling and the process of mRNA translation initiation. We found that decreases in androgen receptor activity lead to a compensatory increase in the activity of the eIF4F translation initiation complex which drives hormone signaling independence in CRPC. Importantly, this is mediated through the translation of distinct subsets of mRNAs. Based on these findings, we hypothesize that aberrant mRNA translation of distinct gene networks enables resistance to nuclear hormone receptor inhibition and CRPC progression. Our long-term objective is to utilize state-of-the-art patient derived models, ribosome profiling, and next-generation translation inhibitors 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 how alterations in mRNA translation initiation promote resistance to AR pathway directed therapies, and 2) delineate the translational gene networks that promote resistance to AR signaling inhibitors. Ultimately, these studies are poised to uncover a new paradigm for gene regulation in nuclear hormone receptor inhibitor resistance and provide the preclinical basis for targeting the protein synthesis apparatus in an increasingly common and highly aggressive disease.

项目概要/摘要本申请是为了响应被识别为 NOT-CA- 的特殊利益通知 (NOSI) 而提交的 20-014。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不幸的是，它会导致患者产生新的致命性前列腺癌表型。尤其，对恩杂鲁胺和阿比特龙等疗法具有耐药性的去势抵抗性前列腺癌 (CRPC) 患者中的发生率正在增加，并且都是致命的。治疗的主要障碍进展是由于缺乏相关的疾病模型，并且对导致疾病发生的机制了解甚少。上升到这种表型。长期以来，蛋白质合成过程一直被认为服从于基因的改变。癌症病因学中的 DNA 和 RNA 水平。然而，我们实验室和其他实验室的工作表明蛋白质合成控制是一个动态过程，不仅协调大量 mRNA 翻译，还协调对癌症表型很重要的不同 mRNA 的专门翻译。最近，我们的实验室发现了雄激素受体信号传导与雄激素受体之间的新功能联系。 mRNA翻译起始过程。我们发现雄激素受体活性的降低会导致驱动激素信号转导的 eIF4F 翻译起始复合物的活性代偿性增加 CRPC 的独立性。重要的是，这是通过不同 mRNA 子集的翻译来介导的。基于这些发现，我们假设不同基因网络的异常 mRNA 翻译使得抵抗核激素受体抑制和 CRPC 进展。我们的长期目标是利用最先进的患者衍生模型、核糖体分析和下一代翻译抑制剂明确研究雄激素受体与蛋白质合成控制之间的基本联系与前列腺癌患者高度相关的新出现的疾病过程。为此，我们将解决以下目标：1) 确定 mRNA 翻译起始的改变如何促进对 AR 途径的抵抗定向治疗，2) 描绘促进 AR 信号传导抵抗的翻译基因网络抑制剂。最终，这些研究有望揭示核激素受体基因调控的新范式抑制剂耐药性并为靶向蛋白质合成装置提供临床前基础日益常见且高度侵袭性的疾病。