Defining the role of eIF4F in metastatic castration resistant prostate cancer

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新标志。包括PI 3 K-AKT-mTOR和MYC致癌信号传导途径在内的蛋白质合成的主要调节剂汇聚在帽结合复合物eIF 4F上，以调节整体蛋白质合成和特定mRNA的翻译。在人类癌症中，eIF 4F复合物的组分异常表达并与不良预后相关。利用遗传学方法，Hsieh博士最近发现eIF 4F复合物的超活化是体内AKT介导的肿瘤发生所必需的。此外，他还在前列腺癌中鉴定了一组eIF 4F调节的促侵袭mRNA（YB-1，MTA-1，CD 44和波形蛋白），这些mRNA是肿瘤侵袭和转移所必需的，他表明这些mRNA可以被抑制，具有显著的临床前疗效。由于PI 3 K-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，因此他假设这些通路会聚于eIF 4F，以引发基因表达的特定节点的异常翻译，从而驱动从局部激素敏感性前列腺癌向转移性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eIF 4F介导的翻译进行生物体，细胞和分子询问。这项建议的目的是：1）确定eIF 4F活性亢进增强YB-1、MTA-1、CD 44和波形蛋白翻译以促进前列腺癌细胞侵袭（CRPC的关键特征）的机制，2）确定eIF 4F复合物对CRPC发展和维持的作用。本研究的目的是使用新的遗传学，蛋白质组学，先进的共聚焦显微镜和治疗方法，以确定通过eIF 4F启动和维持转移性CRPC的翻译控制失调的机制，以及治疗意义。 Hsieh博士是UCSF血液学/肿瘤学部门的讲师，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。Ruggero博士和Hsieh博士开发了一个研究和培训平台，这将使Hsieh博士能够领导自己的独立研究企业。他将利用Ruggero实验室的资源，通过课堂工作和合作获得先进的共聚焦显微镜，质谱和人类前列腺组织病理学的正式培训，并从世界级的K 08咨询委员会获得额外的指导。最终，他将作为K 08获奖者接受的出色培训将为他提供坚实的基础，以作为一名医生科学家启动独立的研究计划。!

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. !