Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity.
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.
Graff
Jeremy R
JR
Lilly Research Labs, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. graff_jeremy@lilly.com
Konicek
Bruce W
BW
Vincent
Thomas M
TM
Lynch
Rebecca L
RL
Monteith
David
D
Weir
Spring N
SN
Schwier
Phil
P
Capen
Andrew
A
Goode
Robin L
RL
Dowless
Michele S
MS
Chen
Yuefeng
Y
Zhang
Hong
H
Sissons
Sean
S
Cox
Karen
K
McNulty
Ann M
AM
Parsons
Stephen H
SH
Wang
Tao
T
Sams
Lillian
L
Geeganage
Sandaruwan
S
Douglass
Larry E
LE
Neubauer
Blake Lee
BL
Dean
Nicholas M
NM
Blanchard
Kerry
K
Shou
Jianyong
J
Stancato
Louis F
LF
Carter
Julia H
JH
Marcusson
Eric G
EG
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