Anti-Tumor Activity Of The Eif4e-Targeted Drug Ribavirin In Breast Cancer Cells

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC In this study, we explored the potential of targeting the eukaryotic translation initiation factor (eIF4E) with ribavirin as a novel anti-tumor agent in breast cancer. eIF4E is an oncogene that facilitates nuclear export and translation of specific, growth-stimulatory mRNAs, including cyclins, c-myc, survivin, VEGF and others, thereby promoting cell survival. Overexpression of eIF4E also leads indirectly to activation of Akt, providing a positive feed-back loop for eIF4E activation and Akt signaling effects. Ribavirin is an antiviral drug that has been shown to inhibit oncogenic transformation mediated by eIF4E and reduce the clonogenic potential of cancer cells with high eIF4E levels. Ribavirin specifically inhibits translation and/or nuclear export of eIF4E targets in cells both in vitro and in patients, as shown in a recent phase I/II proof-of-principle trial in patients with AML. In this trial, dramatic clinical improvements were observed and reductions in eIF4E levels and activity correlated with clinical response. Importantly, ribavirin is largely non-toxic even at high doses, possibly due to an eIF4E oncogene addiction specific to tumor cells. eIF4E is overexpressed in more than 50% of breast cancers, and high levels are associated with increased angiogenesis, clinical progression and poor prognosis. Targeting eIF4E with ribavirin may therefore be an attractive therapeutic strategy for this malignancy. We studied the effects of ribavirin in a panel of breast cancer cells, representing luminal and basal-type tumors with various ER, PR and Her2 status. Western blot analysis showed that eIF4E was overexpressed compared to normal breast tissue and predominantly cytoplasmic in all of the cell lines. In addition, we examined eIF4E levels in metastatic skin lesions of three breast cancer patients and found highly elevated levels compared to normal skin. Ribavirin anti-proliferative activity was assessed using a cell viability assay and clonogenic assays were performed to examine changes in both anchorage dependent and -independent growth. At clinically relevant concentrations, the majority of the cell lines responded to ribavirin, with varying sensitivity. Inhibition of cell growth was associated with decreased protein levels of eIF4E targets such as cyclin D1 and survivin, and a reduction in phosphorylation of Akt as well as eIF4E binding protein 1 (4E-BP1) were observed. Cell cycle analysis showed that ribavirin caused a significant S-phase arrest in sensitive cells, while apoptosis was only observed at elevated concentrations of the drug. This data encourages further study of ribavirin as a breast cancer therapeutic and identification of potential combination regimens. A clinical trial of single agent ribavirin in patients with advanced metastatic breast cancer is planned in the near future. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3165.