The eIF4F translation initiation complex, and particularly its subunit eIF4E, plays a central role in tumorigenesis through gene amplification, oncogene regulation, and direct contributions to tumour progression. Beyond its canonical function in translation initiation, eIF4E also mediates nuclear mRNA export, which may be especially critical in cancer due to the high oncogene-driven transcriptional burden, this may create cancer-specific vulnerabilities that can be therapeutically exploited.
Hypothesis: Targeting cancer cell dependency on the translation initiation or mRNA export roles of eIF4E will suppress tumour cell growth and survival and inform on potential therapeutic strategies.
· Aim 1 Define functional contributions in cancer v normal cells. Using a comprehensive library of eIF4E mutants in genetic rescue models experiments we will determine how its translation and mRNA export functions contribute to cancer cell survival, revealing dependencies unique to cancer and the function of potentially druggable sites on eIF4E.
· Aim 2. Advance eIF4E-targeted drug discovery. Use a combination of genetic models and small-molecule tool compounds to identify features of eIF4E required for its oncogenic activity and assess their promise as therapeutic targets.
· Aim 3: Role of eIF4E in the pioneer round of protein synthesis. Test cancer cell dependency on eIF4E for the initial, pioneer, round of translation and sustaining oncogene-associated protein synthesis, while exploring eIF4E-independent mechanisms as a source of resistance to eIF4E-targeted therapies.
Overall impact: The output from this planned research will clarify the distinct biological roles of eIF4E and associated translational mechanisms in cancer and uncover potential vulnerabilities exploitable for therapy. Insights from AIMS1-3 will directly inform the development of innovative strategies to disrupt eIF4E-mediated processes, providing a foundation for next-generation cancer treatments.
Candidates must have, or be on track to receive, a First- or Upper Second- class Honours degree (or a Masters) in Biological sciences or related subject area and have experience in cellular and/or molecular biology, and must have a basic knowledge of cancer cell biology and/or gene expression regulation.
