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Effective Treatment of Tumors with Strong ß-Catenin/T-Cell Factor Activity by Transcriptionally Targeted Oncolytic Herpes Simplex Virus Vector

Molecular Neurosurgery Laboratory, Department of Neurosurgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts

Requests for reprints: Toshihiko Kuroda, 185 Cambridge Street, CPZN-3800, Boston, MA 02114. Phone: 617-643-3384; Fax: 617-643-3422; E-mail: kuroda{at}helix.mgh.harvard.edu or tokuroda-gi{at}umin.ac.jp.

The Wnt/ß-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 ß-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 ß-catenin/Tcf signaling. Intratumoral injection of bM24-TE significantly reduced the growth of highly ß-catenin active SW480 CRC tumors and induced a complete response in half of them, whereas it had no effect on the growth of ß-catenin-inactive A549 tumors. Our results suggest that a transcriptionally regulated oncolytic herpes vector targeting ß-catenin/Tcf signal is very efficacious against CRC tumors carrying an APC gene mutation between the first and second 20-amino-acid repeats. (Cancer Res 2006; 66(20): 10127-35)