Mining the Wnt pathway for cancer therapeutics

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Abstract
Aberrant activation of the Wnt pathway is implicated in driving the formation of various human cancers, particularly those of the digestive tract. Blocking this aberrant Wnt pathway activity in cancer cell lines efficiently inhibits their growth. Drugs designed to achieve this in the clinic are therefore predicted to be effective cancer therapeutics. Long-term use of conventional non-steroidal anti-inflammatory drugs (NSAIDS) including aspirin might reduce the risk of developing some forms of cancers, including those driven by aberrant Wnt signalling activity. Studies using cancer cell lines and mouse models of colon cancer indicate that these NSAIDS might partially block cancer cell growth by reducing aberrant Wnt signalling activity. Vitamins A and D derivatives are thought to have anticancer properties. This might be partly attributed to reduction of aberrant Wnt signalling in cancer cells through poorly defined mechanisms that include activation of nuclear receptors capable of reducing Tcf–β-catenin complex formation. Preliminary studies indicate that antibodies specific for Wnt pathway components such as Wnt ligands or Frizzled receptors may effectively inhibit aberrant Wnt signalling in some Wnt-addicted cancers. Preliminary results indicate that viral-based strategies targeting cancers with constitutive Wnt signalling have potential as effective cancer therapies. Strategies include generating oncolytic viruses that selectively replicate and kill cancer cells with high levels of Wnt signalling, and designing viruses that selectively express cytotoxic genes in these cancer cells. High-throughput screening and structure-based design programs have identified small-molecule compounds capable of inhibiting aberrant Wnt signalling activity in cancer cells by blocking the formation of key protein complexes such as Tcf–β-catenin. Future challenges will be to improve on the selectivity and in vivo efficacy of these small-molecule inhibitors. Identification of the Tcf–β-catenin target gene program inappropriately activated in Wnt-driven cancers should facilitate selection of novel targets for therapeutic antibodies or small-molecule inhibitors.