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. !
Metastatic castration resistant prostate cancer (CRPC) is incurable and requires a re-examination of fundamental mechanisms that drive the formation of this deadly disease for the development of innovative treatment strategies. In this grant, I propose to make the first functional connection between abnormal reprogramming of the protein synthetic machinery and the development and progression of metastatic CRPC. This study is poised to deliver a new paradigm for the treatment of incurable metastatic CRPC, provide new therapeutic targets centered on the translation initiation apparatus, and identify important functional biomarkers to accurately predict for aggressive disease and to monitor for treatment response.!
