title: Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity.
abstract: 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.
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. graff_jeremy@lilly.com
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Graff
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Konicek
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Vincent
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Lynch
authors.forename: David
authors.initials: D
authors.lastname: Monteith
authors.forename: Spring N
authors.initials: SN
authors.lastname: Weir
authors.forename: Phil
authors.initials: P
authors.lastname: Schwier
authors.forename: Andrew
authors.initials: A
authors.lastname: Capen
authors.forename: Robin L
authors.initials: RL
authors.lastname: Goode
authors.forename: Michele S
authors.initials: MS
authors.lastname: Dowless
authors.forename: Yuefeng
authors.initials: Y
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Sean
authors.initials: S
authors.lastname: Sissons
authors.forename: Karen
authors.initials: K
authors.lastname: Cox
authors.forename: Ann M
authors.initials: AM
authors.lastname: McNulty
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Parsons
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Lillian
authors.initials: L
authors.lastname: Sams
authors.forename: Sandaruwan
authors.initials: S
authors.lastname: Geeganage
authors.forename: Larry E
authors.initials: LE
authors.lastname: Douglass
authors.forename: Blake Lee
authors.initials: BL
authors.lastname: Neubauer
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Dean
authors.forename: Kerry
authors.initials: K
authors.lastname: Blanchard
authors.forename: Jianyong
authors.initials: J
authors.lastname: Shou
authors.forename: Louis F
authors.initials: LF
authors.lastname: Stancato
authors.forename: Julia H
authors.initials: JH
authors.lastname: Carter
authors.forename: Eric G
authors.initials: EG
authors.lastname: Marcusson
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D014176:Protein Biosynthesis / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays