OCT 29, 2014 07:30 AM PDT

Targeting the oncogene eIF4E in leukemia reveals a new form of drug resistance

Speakers
  • 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 an oncogene elevated in an estimated 30% of cancers. The traditional view is that eIF4E drives proliferation and survival by increasing the translation of a subset of mRNAs encoding proteins involved in these processes. eIF4E also promotes the nuclear cytoplasmic mRNA export of a subset of growth promoting transcripts. This enables eIF4E to elevate the cytoplasmic concentration of these transcripts and thus their protein levels without a priori altering their translation. Indeed, the mRNA export function of eIF4E contributes to its oncogenic potential. eIF4E requires specific mRNA elements and co-factors to act in mRNA export and also modulates the nuclear pore complex to enable this activity. In acute myeloid leukemia (AML), the nuclear localization and mRNA export function of eIF4E is highly elevated. NMR, mass spectrometry and other biophysical studies demonstrate that ribavirin directly binds and inhibits eIF4E. In the first two clinical studies to ever target eIF4E, ribavirin led to molecular targeting of eIF4E activity, and substantial responses including remissions in relapsed and refractory AML patients. Eventually all responding patients relapsed, analysis of patients specimens revealed a novel form of drug resistance: Gli1 inducible drug glucuronidation. Indeed, this form of resistance was also relevant to the standard of care for AML, cytarabine. New clinical studies targeting eIF4E and this form of drug resistance using Gl1i inhibitors are planned.

    Learning objectives:
     

    • The learner will be able to explain that targeting the oncogene eIF4E with ribavirin has clinical benefits in at least some patients
    • The learner will be able to describe that there is a new form of drug resistance, inducible drug glucurondiation, which is targetable and is like relevant beyond ribavirin and cytarabine

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