Tumour-selective transcriptional targeting for breast cancer gene therapy

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One of the most attractive ways of targeting gene therapy is by exploitation of the transcriptional regulatory elements of genes which display tissue- or tumour-selective patterns of expression. In our Unit we have focused on identifying the key regulatory elements in a small number of genes known to be overexpressed in breast tumours. Shortly, however, the power of expression profiling by chip technology will expand the range of candidate genes enormously. This will also allow much more specific expression-targeting constructs to be developed by `mixing and matching' elements from different genes.

Genetic prodrug activation therapy (GPAT) depends on the conditional expression of a gene encoding an enzyme capable of converting a non-toxic prodrug into an active cytotoxic agent. We have developed prototype systems based on the proximal promoter of the human ERBB2 oncogene driving a variety of suicide genes in plasmid, retroviral and adenoviral vectors. We have completed a phase 1 clinical trial of direct intratumoral injection of an ERBB2-cytosine deaminase plasmid in patients with advanced breast cancer, and the system is about to be applied to other tumour types. Tissue-selective targeting has also been explored using the promoter and enhancer elements of the MUC1 gene, characteristically expressed by simple ductal epithelial cells including those of the breast and pancreas. Combination of the MUC1 and ERBB2 elements has proved effective in generating constructs with dual specificity targeting. In addition, the range of suicide genes which can be delivered with such targeting devices can be expanded by the use of high capacity adenoviral vectors, which allow combinations of suicide genes to be expressed and thus increase therapeutic effect without loss of selectivity.