Targeting Gene Therapy for Prostate Cancer

Abstract

Gene therapy is rapidly emerging as a viable clinical strategy to treat prostate cancer. New developments, such as targeted expression of therapeutic genes, and viruses that are designed to selectively replicate in prostate cancer cells have led to vectors with improved safety, even in elderly male patients. This review describes the various different viral and non-viral strategies employed to date, with a summary of current clinical trials. The main focus of the review is a discussion of the need, and the potential methods that can be used for targeted expression of the therapeutic gene specifically to prostate tumours and metastases. This includes methods of abrogating vector transduction of non-specific tissues, enhancement of transduction into prostate tumour tissue, transcriptional control of the therapeutic gene and some examples of prostate cancer-specific therapeutic genes. We also consider the future of prostate cancer gene therapy and the factors that should be taken into account when designing clinical trials, in a field that is expected to impact on clinical management of a common tumour type.

Human osteocalcin: a strong promoter for nitric oxide synthase gene therapy, with specificity for hormone refractory prostate cancer

“…The main drawbacks with non-viral vectors are low transfection efficiency and expression of transgene [13]. However, the production of NO · presents an apoptotic gene therapy strategy that has a considerable by-stander effect as demonstrated in our previous studies [37][38][39][40].…”

“…The UK accounts for 11% of all gene therapy trials since 1989 (n = 123) with prostate cancer gene therapy ranking second to melanoma for phase I clinical trials in the USA [12,13]. The key consideration in gene therapy is targeting of tumours, especially in metastatic disease.…”

Antisense oligodeoxynucleotides targeting the serine/threonine kinase Pim-2 inhibited proliferation of DU-145 cells

“…It is now well established that the progression of epithelial cells in the prostate from normal to dysplastic or adenomatous epithelium to carcinoma in situ and finally to invasive carcinoma is the result of the sequential accumulation of genetic abnormalities involving oncogenes and tumor suppressor genes. A number of genetic mutations are found in prostate cancer, including activating mutations of the Pim-2 oncogene and loss of the tumor suppressor gene P 53 [1][2][3][4][5] . In the present study, our antisense compounds could downregulate the expression of target mRNA level in vitro, as well as display certain antitumor activity.…”

“…To date a number of the genes associated with prostate cancer formation and progression have been identified, which are deregulated or abnormally overexpressed contributing to tumor formation. Recent technological developments have paved the way for the identification of the genes PRC17, Stat3, and Pim [1][2][3][4][5] . Identification of these genes provides a new target for prostate cancer therapy.…”

Gene Directed Enzyme-Prodrug Therapy

“…In the third step, a prodrug is administered systemically and absorbed by the same cell; the prodrug can then be converted to a cytotoxic drug by the enzyme inside the cell. Because gene expression may be controlled by tumor cell-specific promoters, the enzyme and its associated enzymatic reaction can be precisely predisposed to tumor cells, leaving other cells unaffected even if they engulf the gene and the prodrug (1)(2)(3)(4). As the result of this preferential conversion of prodrugs to drugs, toxic drugs are only produced in tumor cells while having minimal exposure to healthy cells.…”