High-level, beta-catenin/TCF-dependent transgene expression in secondary colorectal cancer tissue

There is an urgent need for improved therapies for inoperable metastatic co lon cancer. Gene-directed enzyme prodrug therapy (GDEPT) using adenovirus v ectors works well in preclinical models of this disease, but successful cli nical application is hampered by an inability to construct vectors that exp ress at high levels in infected tumor cells but not in infected normal cell s. Constitutive activation of beta -catenin-dependent gene expression is al most certainly a key causative event in the genesis of colon and some other cancers. Here we have exploited this oncogenic defect to design a syntheti c promoter, CTP1, that, in contrast to currently available tumor-selective promoters, is both highly active in cancer cells and highly can cer-cel I-s pecific. CTP1 directs high-level P-galactosidase expression in freshly isol ated biopsies of secondary colon cancer, but is not detectably active in as sociated normal liver tissue. We also demonstrate that CTP1 can direct high -level, tumor-specific therapeutic gene expression in vivo. Intratumoral in jection of an adenovirus vector encoding Escherichia coli nitroreductase dr iven by CTPI efficiently sensitized SW480 xenografts to the prodrug CB1954, whereas systemic vector and prodrug administration produced no apparent si gns of toxicity. CTP1 may form the basis for effective, targeted gene thera py of metastatic colon cancer and other tumors with deregulated beta -caten in/T cell factor.