Regulation of the prostate-specific hTGP (TGM4) gene and its potential use for prostate cancer gene therapy

Prostate cancer is a very important health problem in the UK and worldwide. Available treatments such as radiotherapy, surgery and androgen ablation have failed to significantly increase the life expectancy of prostate cancer patients. Therefore researching new treatments is paramount. A promising approach for prostate cancer is suicide gene therapy. In this work, the use of the NTR/CB1954 enzyme/prodrug system delivered by a baculovirus vector was investigated for its application in prostate cancer cell lines and prostate primary epithelial cultures. The results suggest that the NTR/CB1954 system is highly efficient in causing cell death in prostate cell lines and prostate primary epithelial cultures. The use of a baculovirus vector to deliver the NTR gene resulted in increased transduction of prostate cancer cell lines in comparison to non-malignant prostate and non-prostate cell lines. To target NTR expression to prostate cells the regulation of the hTGP promoter was dissected. hTGP expression was confirmed to be highly prostate specific and mainly regulated by retinoic acid, androgens, retinoic acid receptor gamma and the androgen receptor. This work presents the first evidence of an interaction between these nuclear receptors and challenges the current model for prostate specific expression. Finally a baculovirus encoding the NTR gene under the control of the hTGP promoter was tested in prostate cancer cell lines resulting in moderate cell death. These findings are very encouraging but in order to use the hTGP promoter for gene therapy there needs to be further manipulation of the sequence to optimise its potency while maintaining its prostate specificity. The use of NTR and baculovirus coupled to the targeting controlled provided by the hTGP promoter could develop into a potent and specific approach to treat prostate cancer.