Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin
| Autor: | Sarit Assouline, Abdellatif Amri, Denis-Claude Roy, Biljana Culjkovic, Nathalie Beslu, Caroline Rousseau, Stephen Caplan, Katherine L. B. Borden, Eftihia Cocolakis, Wilson H. Miller, Brian Leber |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Male medicine.medical_specialty Myeloid Immunology Biochemistry chemistry.chemical_compound Internal medicine Ribavirin medicine Initiation factor Humans Aged Hematology Oncogene business.industry EIF4E Myeloid leukemia Cell Biology Middle Aged medicine.disease Leukemia Leukemia Myeloid Acute medicine.anatomical_structure Eukaryotic Initiation Factor-4E chemistry Cancer research Female business |
| Zdroj: | Blood. 114(2) |
| ISSN: | 1528-0020 0055-9091 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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