OCT 29, 2014 7:30 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

    Show Resources
    You May Also Like
    SEP 05, 2019 4:00 PM CEST
    C.E. CREDITS
    SEP 05, 2019 4:00 PM CEST
    DATE: September 5, 2019TIME: 7:00am PT, 10:00am ET, 4:00pm CEST PCR (Polymerase Chain Reaction) has gone through a massive evolution since its development in 1983. Besides it...
    AUG 27, 2019 9:00 AM PDT
    C.E. CREDITS
    AUG 27, 2019 9:00 AM PDT
    DATE: August 27, 2019 TIME: 9:00am PDT, 12:00pm EDT Immunotherapies targeting PD-1 or PD-L1 have proven remarkably effective for treating cancer in some patients, with considerabl...
    FEB 26, 2020 9:00 AM PST
    Add to Calendar Select one of the following: iCal Google Calendar Outlook Calendar Yahoo Calendar
    C.E. CREDITS
    FEB 26, 2020 9:00 AM PST
    Add to Calendar Select one of the following: iCal Google Calendar Outlook Calendar Yahoo Calendar
    DATE: February 26, 2020 TIME: 9:00am PST 3D cell culture and analysis and the study of organoids and spheroids are becoming more prevalent as a research method in publications as traditional...
    JAN 23, 2020 9:00 AM PST
    C.E. CREDITS
    JAN 23, 2020 9:00 AM PST
    DATE: January 23, 2020 TIME: 9:00am PST, 12:00pm EST...
    FEB 19, 2020 11:00 AM PST
    C.E. CREDITS
    FEB 19, 2020 11:00 AM PST
    DATE: February 19, 2020TIME: 11:00am PST, 2:00pm EST...
    OCT 02, 2019 11:00 AM PDT
    OCT 02, 2019 11:00 AM PDT
    DATE: October 2, 2019TIME: 11:00am PDT, 2:00pm EDT Ditch the Excel spreadsheets and manage your molecular workflows entirely in your LIMS Achieve configuration of molecular workf...
    Loading Comments...
    Show Resources