A major limiting factor in anti-neoplastic therapy is the failure of some tumor types to respond to anticancer treatments, and the appearance of resistant cell populations in originally responsive malignancies upon relapse. There is a large body of evidence that genetic changes leading to increased cap-dependent translation are accompanied by cancer cell chemoresistance and are associated with a poor prognosis. We have recently discovered that inhibiting assembly of the cap-dependent translation initiation apparatus eIF4F, (a trimolecular complex of eIF4G, eIF4A and eIF4E) in Ras Vl2 transformed cells by transfer of the gene encoding translational repressor 4E-BPl (which sequesters eIF4E, the 5? mRNA cap binding protein), sensitizes these cells to non-genotoxic and genotoxic cytostatic drugs in vitro, and dramatically reduces their tumorigenicity. Most importantly from a therapeutic point of view, we have found that disruption of eIF4F assembly specifically activates apoptosis in cancer cells, but not in non-transformed cells, identifying eIF4F as a potential novel molecular target for anticancer drug discovery . Thus, here we propose to test the hypothesis that phosphoramidate nucleotide derivatives that repress cap-dependent translation initiation by interfering with the interaction between the 5? rnRNA cap and eIF4E will activate apoptosis in a wide spectrum of cancer cells with an upregulated translation apparatus; and sensitize them to safe doses of chemotherapeutic agents without harming desirable bystander cells.
Our Aims i nclude:
Aim 1. Synthesize a library of nucleotides predicted to inhibit binding of eIF4E to the 5? rnRNA cap;
Aim 2. Test candidate compounds in an ordered series of high and medium throughput in vitro assay systems;
Aim 3. Utilize preclinical models of breast and lung cancer to test the most promising compound (based on Aim 2 results) for its ability to collaborate with well-tolerated doses of available cancer therapeutics to inhibit xenograft growth in athymic mice. To achieve these aims, we have assembled an experienced investigative team committed to anticancer drug discovery .
