Replicating adenoviruses that target tumors with constitutive activation of the wnt signaling pathway

Despite important advances in understanding the molecular basis of cancer, few treatments have been devised which rationally target known causal oncog enic defects. Selectively replicating viruses have a major advantage over n onreplicating viruses to target these defects because the therapeutic effec t of the injected virus is augmented by virus produced within the tumor. To permit rational targeting of colon tumors, we have developed replicating a denoviruses that express the viral E1B and E2 genes from promoters controll ed by the Tcf4 transcription factor. Tcf4 is constitutively activated by mu tations in the adenomatous polyposis coli and beta -catenin genes in virtua lly all colon tumors and is constitutively repressed by Groucho and CtBP in normal tissue. The Tcf-E2 and Tcf-E1B promoters are active in many, but no t all, cell lines with activation of the wnt pathway. Viruses with Tcf regu lation of E2 expression replicate normally in SW480 colon cancer cells but show a 50- to 100-fold decrease in replication in H1299 lung cancer cells a nd WI38 normal fibroblasts. Activation of wnt signaling by transduction of a stable beta -catenin mutant into normal fibroblasts renders the cells per missive for virus replication. Insertion of Tcf4 sites in the E1B promoter has only small effects on replication in vitro but significantly reduces th e inflammatory response in a rodent lung model in vivo. Replicating adenovi ruses with Tcf regulation of both E1B and E2 transcription are potentially useful for the treatment of liver metastases from colorectal tumors, but ad ditional changes will be required to produce a virus that can be used to tr eat all colon tumors.