The Wnt/
beta-catenin/
T-cell factor (Tcf) pathway is aberrantly up-regulated in the majority of
colorectal cancers (CRC) and
hepatoblastomas due to either an APC or
beta-catenin gene mutation. We constructed synthetic promoters, T and TE, which contain tandem repeats of a Tcf responsive
element without and with the human 4F2 gene intronic enhancer, respectively. Although the T and TE promoters showed higher transcriptional activity than a control promoter in all CRC and
hepatoblastoma cell lines tested, with low activities in most other tumor cell lines, the level of transcription varied considerably among the CRC and
hepatoblastoma cell lines. In some CRC cell lines, the TE promoter displayed higher levels of transcription than even the human CMV(IE) promoter. In those CRC cells, the APC gene mutations were located within a small segment between the first and second 20-amino-acid repeats in the mutation cluster region of the APC
protein. We created a transcriptionally targeted oncolytic herpes simplex virus vector (bM24-TE) in which replication is driven by the TE promoter. This vector efficiently and specifically replicated in and killed
tumor cells with strong
beta-catenin/Tcf signaling. Intratumoral injection of bM24-TE significantly reduced the growth of highly
beta-catenin active SW480 CRC
tumors and induced a complete response in half of them, whereas it had no effect on the growth of
beta-catenin-inactive A549
tumors. Our results suggest that a transcriptionally regulated oncolytic herpes vector targeting
beta-catenin/Tcf signal is very efficacious against CRC
tumors carrying an APC gene mutation between the first and second 20-amino-acid repeats.