A conditionally replicating adenovirus targeted to tumor cells through activated RAS/P-MAPK-selective mRNA stabilization

Speaker：鄭至暐                                      Time：2003/11/26

Commentator：蕭璦莉 老師                             Place：Room 601

Abstract：

The effective targeting of replication-selective oncolytic viruses, which are a rapidly expanding therapeutic platform for cancer, is essential when it is used for cancer treatment. Here, the authors proposed a new strategy to achieve the selection of tumor cells through the mRNA stabilization in tumor cells. It has been proven that the ligation of COX-2 3’ UTR to mRNA would decline the mRNA expression to negligible level. Nevertheless, if the cells’ RAS/P-MAPK pathway was activated, the stability of mRNA would increase instead. The authors described an adenovirus, Ad-E1A-COX, in which its essential early gene E1A is regulated by ligation to COX-2 3’ UTR. With RAS/P-MAPK pathway activation, Ad-E1A-COX-infected RIE-iRAS cells (contains a stably integrated, IPTG inducible Ha-ras^Val12 cDNA

)   produced in excess of 3 logs more viruses than the same culture with low RAS/P-MAPK pathway activity. The results showed that the Ad-E1A-COX virus is preferentially oncolytic in vitro in human tumor cells with high P-MAPK activity. In in vivo experiments, the authors used histologically closely matched glioma cell lines that differ in P-MAPK activity, and the results are consistent with the in vitro data demonstrating a strong correlation between the P-MAPK status of a tumor and its ability to support replication of the Ad-E1A-COX virus. Taken together, these results suggest that the Ad-E1A-COX virus may have therapeutic potential for the treatment of cancer with activated RAS/P-MAPK signaling pathway.

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