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 Blood, 9 July 2009, Vol. 114, No. 2, pp. 257-260.
Prepublished online as a Blood First Edition Paper on May 11, 2009; DOI 10.1182/blood-2009-02-205153.

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CLINICAL TRIALS AND OBSERVATIONS

Brief report

Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin

Sarit Assouline1, Biljana Culjkovic2, Eftihia Cocolakis1, Caroline Rousseau1, Nathalie Beslu2, Abdellatif Amri2, Stephen Caplan1, Brian Leber3, Denis-Claude Roy4, Wilson H. Miller, Jr1, and Katherine L. B. Borden2

1 Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC; 2 Institute for Research in Immunology and Cancer & Department of Pathology and Cell Biology, Université de Montréal, Montréal, QC; 3 McMaster University/Hamilton Health Sciences, Hamilton, ON; and 4 Hôpital Maisonneuve Rosemont, Montréal, QC

The eukaryotic translation initiation factor eIF4E is elevated in 30% of malignancies including M4/M5 subtypes of acute myeloid leukemia (AML). The oncogenic potential of eIF4E arises from its ability to bind the 7-methyl guanosine (m7G) cap on mRNAs, thereby selectively enhancing eIF4E-dependent nuclear mRNA export and translation. We tested the clinical efficacy of targeting eIF4E in M4/M5 AML patients with a physical mimic of the m7G cap, ribavirin. Among 11 evaluable patients there were 1 complete remission (CR), 2 partial remissions (PRs), 2 blast responses (BRs), 4 stable diseases (SDs), and 2 progressive diseases (PDs). Ribavirin-induced relocalization of nuclear eIF4E to the cytoplasm and reduction of eIF4E levels were associated with clinical response. Lack of response or relapse coincided with continued or renewed nuclear localization of eIF4E. This first clinical study to target eIF4E in human malignancy demonstrates clinical activity and associated molecular responses in leukemic blasts. This trial is registered at ClinicalTrials.gov (NCT00559091 [ClinicalTrials.gov] ).


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