Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity

• Published in: The Journal of clinical investigation Vol. 117; no. 9; pp. 2638 - 2648
• Main Authors: Graff, Jeremy R, Konicek, Bruce W, Vincent, Thomas M, Lynch, Rebecca L, Monteith, David, Weir, Spring N, Schwier, Phil, Capen, Andrew, Goode, Robin L, Dowless, Michele S, Chen, Yuefeng, Zhang, Hong, Sissons, Sean, Cox, Karen, McNulty, Ann M, Parsons, Stephen H, Wang, Tao, Sams, Lillian, Geeganage, Sandaruwan, Douglass, Larry E, Neubauer, Blake Lee, Dean, Nicholas M, Blanchard, Kerry, Shou, Jianyong, Stancato, Louis F, Carter, Julia H, Marcusson, Eric G
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.09.2007
• Subjects: Angiogenesis; Animals; Apoptosis; Base Sequence; Biomedical research; Cancer; Cells, Cultured; Clinical trials; Endothelial Cells - metabolism; Eukaryotic Initiation Factor-4E - genetics; Eukaryotic Initiation Factor-4E - metabolism; Gene Expression Regulation, Neoplastic; Genetic aspects; Humans; Lymphoma; Mice; Neoplasms - blood supply; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms - therapy; Neovascularization; Observations; Oncology, Experimental; Protein Biosynthesis - genetics; Proteins; Ribonucleic acid; RNA; Toxicity; Tumors; Xenograft Model Antitumor Assays; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci32044

Expression of eukaryotic translation initiation factor 4E (eIF4E) is commonly elevated in human and experimental cancers, promoting angiogenesis and tumor growth. Elevated eIF4E levels selectively increase translation of growth factors important in malignancy (e.g., VEGF, cyclin D1) and is thereby an attractive anticancer therapeutic target. Yet to date, no eIF4E-specific therapy has been developed. Herein we report development of eIF4E-specific antisense oligonucleotides (ASOs) designed to have the necessary tissue stability and nuclease resistance required for systemic anticancer therapy. In mammalian cultured cells, these ASOs specifically targeted the eIF4E mRNA for destruction, repressing expression of eIF4E-regulated proteins (e.g., VEGF, cyclin D1, survivin, c-myc, Bcl-2), inducing apoptosis, and preventing endothelial cells from forming vessel-like structures. Most importantly, intravenous ASO administration selectively and significantly reduced eIF4E expression in human tumor xenografts, significantly suppressing tumor growth. Because these ASOs also target murine eIF4E, we assessed the impact of eIF4E reduction in normal tissues. Despite reducing eIF4E levels by 80% in mouse liver, eIF4E-specific ASO administration did not affect body weight, organ weight, or liver transaminase levels, thereby providing the first in vivo evidence that cancers may be more susceptible to eIF4E inhibition than normal tissues. These data have prompted eIF4E-specific ASO clinical trials for the treatment of human cancers.