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Purpose of the study: Malignant pleural mesothelioma is a disease with a poor prognosis and a median survival time of only 1 year. Thus, it is very essential to find potential new therapies for mesothelioma and thereby identify new targets regulated by cap-dependent translation in this cancer. 4EGI-1 inhibits the interaction between translation initiation factors eIF4E and eIF4G and thus inhibits cap-dependent translation in other cancers. Here, we study the effect of 4EGI-1 on cap-dependent translation in mesothelioma.
 Methods: Human mesothelioma cell lines H2596 and H2461 and the non-transformed human mesothelial cell line LP9 were used for these studies. Proliferation studies using the Cell Counting Kit-8 were performed. Cap-binding assay using the 7-methyl-GTP-Sepharose resin was done to study the inhibition of the formation of the cap-dependent translation initiation complex. Western blot analysis was used to evaluate the levels of various proteins on treatment of cells with 4EGI-1. Polysome analysis is presently being carried out in order to identify preferentially translated transcripts in cancerous cells compared to cells treated with 4EGI-1.
 Results: Compared to LP9, 4EGI-1 preferentially inhibited the growth of H2596 and H2461. 4EGI-1 also disrupted cap-binding in these cell lines both invitro and in cells. Besides, 4EGI-1 treatment in these cancer cells also lead to a decrease in the protein levels of osteopontin (a known biomarker for mesothelioma) and survivin (an inhibitor of apoptosis). Surprisingly, we also observed that treatment with 4EGI-1 caused an increase in the hypophosphorylated form (active form) of the translational repressor 4EBP-1 in the cancer cells.
 Conclusions: Our studies show that 4EGI-1 can be a possible new strategy for treating mesothelioma. Also, this drug might help to identify new targets preferentially translated by cap-dependent translation in mesothelioma and validate their potential efficacy in treating this disease.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA