Defining the role of eIF4F in metastatic castration resistant prostate cancer

定义 eIF4F 在转移性去势抵抗性前列腺癌中的作用

• 批准号: 8487314
• 负责人: Andrew Caleb Hsieh
• 金额: $ 19.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487314
• 关键词: Address; Advisory Committees; Androgens; Attention; Binding; Biological Markers; CD44 gene; Cancer Biology; Candidate Disease Gene; Cells; Cellular Stress; Clinical; Collaborations; Complex; Confocal Microscopy; Copy Number Polymorphism; Data; Development; Disease; Elements; Environment; Exhibits; Foundations; Future; Gene Expression; Genes; Genetic; Genetic Translation; Genomics; Goals; Grant; Hematology; Histopathology; Hormones; Human; Hyperactive behavior; Individual; International; Laboratories; Lead; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Mediating; Mentors; Mentorship; Mesenchymal; Messenger RNA; Metastatic to; Microtus; Molecular; Monitor; Neoplasm Metastasis; Oncogenic; PTEN gene; Pathway interactions; Peptide Initiation Factors; Pharmacologic Substance; Physicians; Predictive Value; Process; Proliferating; Prostate; Protein Biosynthesis; Proteomics; Proto-Oncogene Proteins c-akt; Pyrimidine; Regulatory Element; Regulon; Research; Research Training; Resources; Ribosomes; Role; Scientist; Signal Pathway; Solid; Technology; Testing; Therapeutic; Tissues; Training; Translation Initiation; Translations; Treatment Efficacy; Tumor Cell Invasion; Vimentin; Work; base; cancer cell; cancer initiation; career; castration resistant prostate cancer; cell motility; cohort; deprivation; genome-wide; human FRAP1 protein; in vivo; inhibitor/antagonist; innovation; instructor; interest; member; mouse model; new therapeutic target; novel; novel therapeutics; oncology; outcome forecast; overexpression; preclinical efficacy; prognostic; programs; prostate cancer cell; synthetic protein; treatment response; treatment strategy; tumor initiation; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Aberrant protein synthesis is an emerging hallmark of oncogenic transformation and cancer progression. Master regulators of protein synthesis including the PI3K-AKT-mTOR and MYC oncogenic signaling pathways converge on the cap-binding complex, eIF4F, to regulate global protein synthesis and the translation of specific mRNAs. In human cancers, components of the eIF4F complex are aberrantly expressed and correlate with poor prognosis. Using genetic approaches, Dr. Hsieh recently discovered that hyperactivation of the eIF4F complex is necessary for AKT-mediated tumorigenesis in vivo. Moreover, he has identified a cohort of eIF4F regulated pro-invasion mRNAs (YB-1, MTA-1, CD44, and vimentin) in prostate cancer necessary for tumor invasion and metastasis, which he showed can be pharmacologically inhibited with significant preclinical efficacy. Since the PI3K-AKT-mTOR and MYC pathways are both deregulated in lethal metastatic castration resistant prostate cancer (CRPC), he hypothesizes that these pathways converge on eIF4F to elicit the aberrant translation of specific nodes of gene expression to drive the transition from localized hormone sensitive prostate cancer to metastatic CRPC. He proposes to leverage his fundamental discoveries of aberrant translational control in cancer toward an organismal, cellular, and molecular interrogation of eIF4F- mediated translation in metastatic CRPC. This proposal will aim to: 1) define the mechanism by which eIF4F hyperactivity enhances YB-1, MTA-1, CD44, and vimentin translation to promote cell invasion in prostate cancer, a key feature of CRPC, and 2) determine the role of the eIF4F complex towards the development and maintenance of CRPC. The goal of this study is to use novel genetics, proteomics, advanced confocal microscopy, and therapeutics to determine the mechanisms by which deregulation of translational control through eIF4F initiates and maintains metastatic CRPC, and the therapeutic implications. Dr. Hsieh is an Instructor in the Division of Hematology/Oncology at UCSF and his proposed mentored research plan will be performed in the laboratory of Dr. Davide Ruggero, an international leader in the fields of mouse genetics and translational control. His long-term career goal is to integrate his scientific and clinical expertise to address fundamental questions regarding the role of aberrant translational control in cancer progression. Drs. Ruggero and Hsieh have developed a research and training platform that will equip Dr. Hsieh to lead his own independent research enterprise. He will take advantage of the resources of the Ruggero lab, obtain formal training in advanced confocal microscopy, mass spectrometry, and human prostate histopathology through class work and collaborations, and obtain additional mentorship from a world-class K08 advisory committee. Ultimately, the outstanding training that he will receive as a K08 awardee will provide him with a solid foundation to initiate an independent research program as a physician-scientist. !

描述(由申请人提供)：异常蛋白质合成是致癌转化和癌症进展的一个新的标志。蛋白质合成的主要调节因子包括PI3K-AKT-mTOR和MYC致癌信号通路，聚集在帽结合复合体eIF4F上，调节全球蛋白质合成和特定mRNAs的翻译。在人类癌症中，eIF4F复合体的成分异常表达，并与不良预后相关。利用遗传学方法，谢博士最近发现，eIF4F复合体的过度激活对于AKT介导的体内肿瘤形成是必要的。此外，他还发现了前列腺癌中一组eIF4F调节的侵袭前mRNA(YB-1、MTA-1、CD44和Vimentin)，这些mRNAs是肿瘤侵袭和转移所必需的，他证明了这些基因可以被药物抑制，具有显著的临床前疗效。由于PI3K-AKT-mTOR和MYC通路在致死性转移性去势抵抗前列腺癌(CRPC)中均被解除调控，他假设这些通路会聚在eIF4F上，诱导特定基因表达节点的异常翻译，从而推动从局部激素敏感型前列腺癌向转移性CRPC的转变。他建议利用他在癌症中异常翻译控制的基本发现，对转移性CRPC中eIF4F介导的翻译进行有机、细胞和分子方面的询问。这项建议旨在：1)明确eIF4F过度激活促进YB-1、MTA-1、CD44和Vimentin翻译以促进前列腺癌细胞侵袭的机制，这是CRPC的关键特征；2)确定eIF4F复合体在CRPC的发生和维持中的作用。这项研究的目的是利用新的遗传学、蛋白质组学、先进的共聚焦显微镜和治疗学来确定通过eIF4F解除翻译控制启动和维持转移的CRPC的机制，以及治疗意义。谢博士是加州大学旧金山分校血液科/肿瘤科的讲师，他提出的指导研究计划将在鼠遗传学和翻译控制领域的国际领先者Davide Ruggero博士的实验室进行。他的长期职业目标是整合他的科学和临床专业知识，以解决有关异常翻译控制在癌症进展中的作用的基本问题。鲁杰罗博士和谢家华已经开发了一个研究和培训平台，这将使谢家华有能力领导自己的独立研究企业。他将利用鲁杰罗实验室的资源，通过课堂作业和合作获得先进的共焦显微镜、质谱学和人类前列腺组织病理学的正式培训，并从世界级的K08咨询委员会获得额外的指导。最终，他将作为K08获奖者接受的出色培训将为他作为一名内科科学家启动独立研究计划奠定坚实的基础。好了！