**7. Clinical implications**

Despite its clear importance in cancer, strategies targeting survivin for oncotherapeutic gain have been rather elusive. The question posed here is whether "nuclear survivin" offers a unique therapeutic window? Now that it has been established that nuclear export is essential for activity of survivin as a tumour promoter, one possibility proposed by Stauber and colleagues, is the development of molecular decoys that interfere with its export by antagonising the NES(s). Potentially this strategy could be used to eliminate survivin and (re)sensitise tumours to current cancer therapies (Knauer et al., 2007; Stauber et al., 2007). Intriguingly in 2005, Otto and co-workers used a HLA-A2 restricted survivin peptide to vaccinate patients with advanced, stage IV melanoma. Serendipitously, the epitope selected was a peptide within the central NES of survivin, 96-104 (Colnaghi et al., 2006). Whether this peptide interfered with nuclear exportation of survivin in vivo was not addressed, but the treatment was well tolerated by patients and importantly it enhanced tumour cell apoptosis and caused regression of metastatic lesions (Otto et al., 2005).

We have taken a different angle, endeavouring to exploit the ability of survivin to accelerate cells into S-phase for therapeutic gain (Suzuki et al., 2000). In brief we infected cells with oncolytic viruses engineered to reproduce only in cells with a defective pRB pathway, in this case ovarian cancer cells. As viruses reproduce in S-phase of the host cell cycle, when we compared efficacy of cell lysis post-infection between control and survivin-NLS expressing cells, a marked increase in cytotoxicity was observed, suggesting that nuclear survivin expression synergised with oncolytic virus potency, to effectively eliminate cancer cells (Connell et al., 2008b). These data from cultured cells are promising, and given that survivin is an essential protein it is likely that its oncotherapeutic potential will be realised in combination strategies like this, rather than as a target for a single agent.
