Project 462208

Our research explores the mechanisms regulating protein synthesis (translation) in cancer cells and how these can be exploited for therapeutic purposes. Specifically, we focus on a key regulator of the protein synthesis pathway, a complex known as eukaryotic initiation factor (eIF) 4F. The activity of eIF4F is deregulated in the majority (>70%) of human cancers and this factor can fuel tumor progression and contribute to drug resistance. The consequences of altered eIF4F activity are to engender changes in the types and levels of proteins synthesized, which in turn fosters the growth and survival needs of an emerging tumor cell. Consequently, tumor cells become addicted to elevated eIF4F levels and this creates a tumor cell-selective vulnerability. My lab has been at the forefront of targeting this process with small molecule drugs and we have identified and characterized three potent classes of inhibitors that function to block one of the eIF4F subunits, eIF4A - an essential molecular motor. The best developed class of eIF4A inhibitors are rocaglates and we have shown these to exhibit potent anti-cancer activity in pre-clinical mouse models and to be well tolerated in vivo. Recently, Effector Therapeutics (no relationship with my lab) has initiated clinical trials with the rocaglate eFT226 - speaking to the clinical relevance of our research program. However, what is currently lacking is a clear understanding of the molecular signatures that render tumor cells sensitivity to these compounds. We therefore wish to define (i) why tumor cells respond differently than normal cells when eIF4F is inhibited, (ii) which part of the oncogenic translation program is sensitive to inhibition of eIF4F activity, and (iii) what represents the most potent approach by which to shut down the oncogenic translation program. These studies will provide a better understanding into the mechanism of action of these potent compounds that are being explored for their anti-cancer activity.