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: 8991399
• 负责人: Andrew Caleb Hsieh
• 金额: $ 11.17万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 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/8991399
• 关键词: Defining; role; eIF4F; metastatic; castration

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）：异常的蛋白质合成是致癌转化和癌症进展的新标志。蛋白质合成的主要调节因子，包括 PI3K-AKT-mTOR 和 MYC 致癌信号传导通路，汇聚于帽子结合复合物 eIF4F 上，以调节整体蛋白质合成和特定 mRNA 的翻译。在人类癌症中，eIF4F 复合物的成分异常表达并与不良预后相关。 Hsieh 博士最近利用遗传方法发现，eIF4F 复合物的过度激活对于 AKT 介导的体内肿瘤发生是必要的。此外，他还确定了前列腺癌中肿瘤侵袭和转移所必需的一组 eIF4F 调节的促侵袭 mRNA（YB-1、MTA-1、CD44 和波形蛋白），他证明这些 mRNA 可以通过药物抑制，并具有显着的临床前疗效。由于 PI3K-AKT-mTOR 和 MYC 通路在致死性转移性去势抵抗性前列腺癌 (CRPC) 中均失调，因此他推测这些通路在 eIF4F 上汇聚，引发特定基因表达节点的异常翻译，从而驱动局部激素的转变前列腺癌对转移性 CRPC 敏感。他建议利用其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、细胞和分子研究。该提案旨在：1) 明确 eIF4F 过度活跃增强 YB-1、MTA-1、CD44 和波形蛋白翻译以促进前列腺癌细胞侵袭（CRPC 的一个关键特征）的机制，以及 2) 确定 eIF4F 的作用eIF4F 复合体致力于 CRPC 的开发和维护。本研究的目标是利用新型遗传学、蛋白质组学、先进共聚焦显微镜和治疗学来确定通过 eIF4F 解除翻译控制引发和维持转移性 CRPC 的机制及其治疗意义。 Hsieh 博士是加州大学旧金山分校血液学/肿瘤学系的讲师，他提出的指导研究计划将在小鼠遗传学和翻译控制领域的国际领导者 Davide Ruggero 博士的实验室中进行。他的长期职业目标是整合他的科学和临床专业知识，解决有关异常翻译控制在癌症进展中的作用的基本问题。博士。 Ruggero 和 Hsieh 开发了一个研究和培训平台，使 Hsieh 博士能够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高级共焦显微镜、质谱和人类前列腺组织病理学方面的正式培训，并获得世界级 K08 咨询委员会的额外指导。最终，他作为 K08 获奖者将接受的出色培训将为他作为一名医师科学家启动独立研究项目奠定坚实的基础。 ！