Targeting the TMPRSS2/ERG fusion mRNA using liposomal nanovectors enhances docetaxel treatment in prostate cancer

Abstract

The TMPRSS2/ERG (TE) fusion gene is present in half of prostate cancers. The TMPRSS2 and ERG junction of the fusion mRNA constitutes a cancer specific target. Although docetaxel-based chemotherapy is the second line of therapy following development resistance to androgen ablation therapies, it is not curative. Therefore, development of nontoxic novel monotherapies for targeting TE mRNA in prostate cancer patients and for increasing the clinical efficacy of docetaxel treatment are needed We evaluated multiple approaches to enhance delivery of TE siRNA containing liposomes including PEGylation,; topical treatment with nitroglycerin to increase permeability and retention: and three different PEG modifications: folate, RGD cyclic peptide and a bFGF fibroblast growth factor receptor-targeting peptide. The efficacy of the optimized TE siRNA liposome in combination with docetaxel was then evaluated in vivo with or without topical nitroglycerin in vivo using a VCaP xenograft model. TE fusion protein knockdown in residual tumors was assessed using Western blotting and immunohistochemistry. In vivo therapeutic targeting of TE fusion gene by systemic delivery of RGD-peptide coated liposomal-siRNA nanovectors led to sustained target silencing, suppressed tumor growth in xenograft models and enhanced the efficacy of docetaxel chemotherapy. Simultaneous application of the vasodilator nitroglycerin to the skin further increased tissue the delivery of siRNA and enhanced target knockdown. TE targeted gene silencing therapy using liposomal nanovectors is a potential therapeutic strategy as a monotherapy and to enhance the efficacy of chemotherapy in patients with advanced prostate cancer.