Inhibitors of translation initiation as cancer therapeutics

Deregulated translation initiation is implicated extensively in cancer initiation and progression. Several translation initiation factors cooperate with known oncogenes, are elevated in human tumors and have been implicated in drug resistance. Consequently, there is a great deal of interest in targeting this process to develop new chemotherapeutics, especially since clinical trial results have been mixed when targeting upstream pathways, such as the mammalian target of rapamycin. Several inhibitors have been characterized over the last 5 years that target the ribosome recruitment phase (eukaryotic initiation factor [eIF]4E [antisense oligonucleotides and 4EGI-I] or eIF4A [pateamine A, hippuristanol and silvestrol]), some of which demonstrate activity in preclinical cancer models. The promise of these inhibitors as chemotherapeutics highlights the importance of targeting this pathway and supports efforts aimed at identifying the most susceptible targets. In addition, the framework in which translation inhibitors would be best employed (i.e., as single agents or as adjuvant therapy) in the clinic remains to be explored systematically. Small-molecule inhibitors of translation initiation are validating the idea that protein synthesis is a legitimate target for curtailing tumor growth.