SEP 13, 2012 10:00 AM PDT

Targeting the oncogene eIF4E at the bench and in the clinic

Speaker
  • Principal Investigator, Structure and Function of the Cell Nucleus research unit, Full Professor, Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Instit
    Biography
      Dr Borden is a full professor at the Institute for Research in Immunology and Cancer at University of Montreal. She obtained her PhD with Fred Richards at Yale University in Molecular Biophysics and Biochemistry and trained in NMR and cell biology in London with Andrew Lane at the National Institute for Medical Research and with Paul Freemont at the Imperial Cancer Research Fund (now Cancer Research UK). She has a long standing interest in combining structural, biophysical and cell biological methods to better understand how dysregulated mRNA metabolism can contribute oncogenesis. Currently, she studies the eukaryotic translation initiation factor eIF4E with particular emphasis on its mRNA export functions. Her biophysical and cell biological studies have identified an inhibitor of eIF4E, ribavirin. Ribavirin has been shown to target eIF4E activity in leukemia patients where this correlates with clinical responses including remissions.

    Abstract

     

    The eukaryotic translation initiation factor eIF4E is a potent oncogene estimated to be elevated in about 30% of human cancers including cancers of the breast, prostate, lung, colon as well as others. eIF4E is also elevated in hematological malignancies including M4 and M5 subtypes of acute myeloid leukemia (AML). eIF4E overexpression leads to oncogenic transformaiton in cell lines and to tumours in animal models. eIF4E plays critical roles in mRNA metabolism via its interactions with the methyl-7 guanosine (m7G) cap on the 5' end of mRNAs. eIF4E is best known for its role in mRNA translation but also plays roles in the export of mRNAs from the nucleus to the cytoplasm. Both of these functions are relevant to its oncogenic potential.

     

    New findings will be discussed with regard to newly defined roles of eIF4E in mRNA export. In particular, the ability of eIF4E to modulate the nuclear pore complex (NPC) in order to enhance the export function of eIF4E. In fact, these studies directly link its transformation capacity to its ability to modulate export of certain mRNAs. Further, these studies demonstrate that certain component of the NPC can suppress eIF4E mediated transformation.

     

    Finally, the clinical findings targeting eIF4E activity will be discussed. Our studies, including new NMR studies show that ribavirin directly binds the m7G cap-binding pocket of eIF4E. Ribavirin represses eIF4E dependent mRNA translation and mRNA export. In a Phase II clinical trial, ribavirin monothreapy treatment led to targeting of eIF4E activity in M4 /M5 AML patients and this correlated to clinical responses in patients. In an ongoing Phase I trial with ribavirin combined with cytarabine, eIF4E targeting and clinical responses have also been observed. Thus targeting eIF4E activity appears beneficial to patients.

     


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