Targeting the Oncogene eIF4E with Ribavirin: A Novel Therapeutic Avenue in Acute Myeloid Leukemia.

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.