Clinical trial: How can we target eIF4E as a model?
Translational Research and Clinical Trials
- Can RNA regulons and eIF4E be targeted in cancer? Promising results with the old anti-viral drug ribavirin
- Can this lead to objective clinical responses? Yes it can, but we need to improve duration and frequency of results. We are exploring the best pathways to target when targeting eIF4E.
- Developed assays for molecular responses for our patients, overcoming the challenges of clinical specimens
Using Crispr/Cas9 to improve eIF4E targeting in the clinic
The following questions are being investigated using eIF4E editing by CRISPR technology in different cell lines and a genome-wide CRISPR screen combined with ribavirin, an inhibitor of eIF4E used in clinical trials.
- Which pathways are synthetic lethal with eIF4E?
- What compensatory mechanisms are in place following CRISPR editing of eIF4E?
- Which genetic markers are correlated with improved response to ribavirin or resistance to this treatment?
- What compounds could be used in combination with ribavirin to further decrease cell proliferation in cell lines and achieve an improved clinical outcome?
How does control of RNA metabolism contribute to cancer?
Study of the eIF4E dependent capping process
We've shown that eIF4E increases the m7G capping efficiency of its export target transcripts and we propose this is through its effects on the capping machinery. Capping is a nuclear process involving the guanylyltransferase RNGTT and the methyltransferase RNMT.
- What is the molecular mechanisms and physiological relevance of eIF4E dependent m7G capping?
- What are the regulatory pathways that control eIF4E dependent capping?
- What is the RNA element that confers capping selectivity?
- Understanding the structural basis for eIF4E-dependent increase in capping?
eIF4E and 3’end processing
- Which co-factors associate with eIF4E to regulate RNA 3’end processing?
- How these eIF4E-associated Ribonucleoproteins complexes evolve in time and space in order to select and process their targets?
- What is the impact of eIF4E-associated 3’end processing on the transcriptome and the related gene expression?
- Does this process contribute to eIF4E-related oncogenic functions?
eIF4E and epitranscriptomics
The elevation of the oncogene eIF4E alters protein expression and contributes to the oncogenic phenotype of the cells.
- Is this elevation functionally linked to the abnormal mRNA methylation observed in cancer cells?
- Can eIF4E affect the m6A methylation machinery and its final output, the cell methylome?
VPg substitutes for the m7G cap to recruit eIF4E
The potyvirus-derived viral genome-linked protein (VPg) is covalently bound to the 5' end of viral genomic RNA and associates with host eIF4E for successful infection.
This study constitutes the first structural study of a potyvirus VPg protein. Here, we demonstrated VPg-RNA conjugates were templates for translation.
- Are there new means for the engagement of eIF4E via the plant potyvirus VPg proteins?
- What are the implications for translation?
- Can these findings reveal new regulators which motors eIF4E around? the human kinesin EG5?
eIF4E reprograms extracellular vesicles
- Is eIF4E a master regulator of cellular vesiculation?
- Is this a novel mechanism underpinning disease progression and therapeutic resistance in eIF4E-high AML patients?
NMR fragment screening
Development of selective inhibitors of UGT enzymes
Understanding mechanisms leading to drug resistance are critical for therapeutics. Our studies have shown some cancers can evade the effects of chemotherapies via induced drug glucuronidation via the UGT families of enzymes.
- We have targeted UGT1A4, responsible for glucuronidation of ribavirin, using an innovative dual screening approach based on NMR fragment screens and in vitro glucuronidation assays.
- Excitingly, we identified 6 fragments that showed selectivity for the UGT1A4 over UGT1A1 in model resistance cell lines.
- Structural analysis reveals an allosteric mechanism, the first ever identified for UGTs.