Targeting the Oncogene eIF4E with Ribavirin: A Novel Therapeutic Avenue in Acute Myeloid Leukemia.
Notice bibliographique
Résumé
Abstract Abstract 2085 Poster Board II-62 Over the past 10 years, the incidence of acute myeloid leukemia (AML) has increased significantly with approximately 15 000 new cases annually. Standard induction chemotherapy consisting of cytarabine (Ara-C) and an anthracycline induces remission rates between 50% and 85%. Unfortunately, the majority of patients who achieve remission will relapse and die from their disease within 2 years, highlighting the need for novel therapeutic targets. The eukaryotic translation factor (eIF4E) is overexpressed in many human malignancies, including AML, and is associated with poor prognosis as well as clinical progression. Ribavirin, an anti-viral molecule, is classically used in the treatment of hepatitis C (with interferon), SARS, RSV, Lassa fever and influenza. Its structure physically mimics the m(7)G cap of mRNA, thus inhibiting eIF4E-induced export and translation of sensitive transcripts. We are carrying out the first clinical trial targeting eIF4E with ribavirin in AML patients. Clinical and molecular efficacy has been evaluated in 13 patients to date. The treatment was well tolerated by all patients with no marked toxicity observed. Importantly, no patients developed hemolytic anemia. We demonstrated that ribavirin effectively induces the relocalization of nuclear eIF4E to the cytoplasm and the reduction of eIF4E as well as its target proteins, including suppression of Akt activation. This led to dramatic clinical improvement, including one complete remission, two partial remissions, two blast responses and four patients with stable disease. Final response data will be presented along with translational correlates. Notably, lack of response or relapse after remission was associated with lack of molecular response in leukemic blasts. Despite the encouraging responses of patient on ribavirin, all patients acquired resistance to therapy and eventually relapsed. Hence, we sought novel therapies to combine with ribavirin in order to overcome resistance and maintain remissions. Using a cell line that overexpresses eIF4E, we screened a library of 5000 known drugs and searched for compounds that synergize with ribavirin to suppress tumor growth. We identified nearly 50 lead compounds, many of which are structurally related, with similar biological activity, and are currently used medically for indications other than cancer. Early clinical observations suggest that combinations of cytotoxic agents lead to substantially better clinical outcomes relative to monotherapies. Furthermore, various drugs that suppress the PI3/Akt pathway were found to sensitize leukemia cells to Ara-C. Thus, we combined Ara-C with ribavirin in vitro, and observed an improved reduction in colony growth of AML specimens. Combination therapy with ribavirin and Ara-C in patients with acute myelocytic leukemia is currently ongoing. Preliminary results will be presented. Disclosures: Borden: Translational Therapeutics: Equity Ownership.
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Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
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