Targeting the oncogene eIF4E at the bench and in the clinic

The eukaryotic translation initiation factor eIF4E is a potent oncogene estimated to be elevated in about 30% of human cancers including cancers of the breast, prostate, lung, colon as well as others. eIF4E is also elevated in hematological malignancies including M4 and M5 subtypes of acute myeloid leukemia (AML). eIF4E overexpression leads to oncogenic transformaiton in cell lines and to tumours in animal models. eIF4E plays critical roles in mRNA metabolism via its interactions with the methyl-7 guanosine (m7G) cap on the 5' end of mRNAs. eIF4E is best known for its role in mRNA translation but also plays roles in the export of mRNAs from the nucleus to the cytoplasm. Both of these functions are relevant to its oncogenic potential.

New findings will be discussed with regard to newly defined roles of eIF4E in mRNA export. In particular, the ability of eIF4E to modulate the nuclear pore complex (NPC) in order to enhance the export function of eIF4E. In fact, these studies directly link its transformation capacity to its ability to modulate export of certain mRNAs. Further, these studies demonstrate that certain component of the NPC can suppress eIF4E mediated transformation.

Finally, the clinical findings targeting eIF4E activity will be discussed. Our studies, including new NMR studies show that ribavirin directly binds the m7G cap-binding pocket of eIF4E. Ribavirin represses eIF4E dependent mRNA translation and mRNA export. In a Phase II clinical trial, ribavirin monothreapy treatment led to targeting of eIF4E activity in M4 /M5 AML patients and this correlated to clinical responses in patients. In an ongoing Phase I trial with ribavirin combined with cytarabine, eIF4E targeting and clinical responses have also been observed. Thus targeting eIF4E activity appears beneficial to patients.