The target eIF4E is part of Isis’ cancer collaboration with Eli Lilly and Company; it is the target of LY2275796 which is currently in Phase 1 studies in cancer patients. This paper, published in the September issue of The Journal of Clinical Investigation, describes recent research from Lilly, Isis and the Wood Hudson Cancer Research Laboratory in the development of eIF4E-specific antisense oligonucleotides (ASOs) and the anti-tumor effects of these ASOs in animals.

eIF4E is a protein involved in tumor progression, angiogenesis and metastasis, including breast, prostate, lung, colon and other cancers. Earlier scientific studies suggested that eIF4E may act as a critical “switch” in cancer progression. eIF4E-specific ASOs were developed to have the necessary characteristics required for use as a systemic anticancer therapy. In cultured cells, eIF4E ASOs successfully repressed the expression of eIF4E and eIF4E-regulated proteins without substantially affecting global protein synthesis. Furthermore, systemic administration of eIF4E ASOs selectively and significantly reduced eIF4E expression in human tumors grown in mouse hosts. Most importantly, the eIF4E ASO treatment significantly suppressed growth of these tumors in mice, and even though these ASOs also targeted mouse eIF4E and did reduce its expression by 80% in the liver, there were no apparent effects on body weight or liver function.

These data provide the first in vivo evidence that cancers may be more susceptible to eIF4E inhibition than normal tissue and have prompted development of an eIF4E-specific ASO drug, LY2275796, which is currently being evaluated in Phase 1 clinical studies for the treatment of human cancers.

Full article: http://www.jci.org/cgi/reprint/117/9/2638

Commentary: http://www.jci.org/cgi/content/full/117/9/2385