Eukaryotic translation initiation factor 4E, eIF-4E, binds the 5’ cap structure of mRNAs and delivers these mRNAs to ribosomes to enable protein translation. A wealth of evidence has now indicated that enhanced eIF4E function selectively upregulates the translation of key growth and survival factors such as cyclin D1 and VEGF. Enhanced eIF4E function is common to many human and experimental cancers and results from increased eIF4E expression coupled to increased phosphorylation of the eIF4E inhibitory binding protein, 4EBP. These data indicate that there is a significant selective pressure to increase the activity of eIF4E, thereby enhancing the translation of potent growth and survival factors that, together, enable malignant progression. We have developed a potent anti-sense oligonucleotide (ASO) that specifically targets both rodent and human eIF4E mRNA for RNAse H-mediated destruction. In cell culture, transfection of this ASO suppresses eIF4E expression in a broad panel of human cancer cell lines. Preliminary analysis of human tumor cells shows that the eIF4E-regulated VEGF and cyclin D1 mRNAs are depleted in polyribosomes, indicating that eIF4E reduction substantially diminishes eIF4E function. Transfection with the eIF4E ASO also depletes eIF4E expression in human umbilical vein endothelial cells (HUVECs) and prevents the formation of vessel-like structures by these HUVECs, suggesting that the eIF4E ASO may suppress angiogenesis. Intravenous administration of this ASO significantly reduces eIF4E expression and significantly suppresses the growth of human breast and prostate cancer xenografts. Microvessel density was also reduced in these xenografts as indicated by immunostaining for Von Willebrand’s factor. IV dosing with this ASO not only reduces eIF4E expression in tumor tissue, but also suppresses the expression of eIF4E in the liver of treated mice up to 95% without overt toxicity. Together, these data indicate that suppressing eIF4E expression may be an effective anticancer strategy and may work, in part, by suppressing tumor-related angiogenesis. Based upon these data, this ASO has been advanced to human clinical trials as a novel, anticancer therapeutic.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]