The Identification of Novel Therapeutic Targets for Prostate Cancer

Landers, Kelly Anne (2007). The Identification of Novel Therapeutic Targets for Prostate Cancer PhD Thesis, School of Medicine , University of Queensland.

       
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Author Landers, Kelly Anne
Thesis Title The Identification of Novel Therapeutic Targets for Prostate Cancer
School, Centre or Institute School of Medicine
Institution University of Queensland
Publication date 2007
Thesis type PhD Thesis
Supervisor Dr Michelle Burger
Abstract/Summary Adenocarcinoma of the prostate is the second most common cause of cancer related deaths in men in the western world. Current curative therapies are directed to localised tumours; thus, extending effective but non-invasive treatments to combat both primary and secondary lesions remains a major challenge. A desirable criterion of any effective prostate cancer therapy is its ability to selectively utilise appropriate molecular targets. The identification of these targets represents the greatest challenge for prostate cancer therapy today. The aim of this project was to identify potential therapeutic targets at the level of mRNA and protein. Molecular targets were identified by examining the expression profiles of prostate cell lines using cDNA microarrays. Expression of the identified genes was verified on patient samples using real time RT-PCR. The gene claudin-4 was found to be significantly over-expressed in patient tumour samples compared with BPH samples. Claudin-4 is part of a large family of integral membrane proteins crucial for tight junction formation and function and is a receptor for the food-poisoning causative agent Clostridium perfringens Enterotoxin (CPE). A large immunohistochemical study conducted within a range of prostate tissue conditions confirmed the localisation of claudin-4 to the cell membrane of epithelial cells between cell-to-cell contact sites. Furthermore, the immunohistochemical data revealed that claudin-4 expression was high in low-grade tumours, low in high-grade tumours and high in prostate cancer metastatic lesions. Functional studies revealed that the over-expression of claudin-4 in prostate cell lines was associated with a reduction in cell migration and independent colony formation. In addition, the cytotoxic effects of CPE on the prostate cell lines were claudin-4 specific and dose dependent. An additional aspect of this study was to investigate the efficacy of using RNA-encoded tumour antigens to induce a DC-mediated T-cell response as an immunotherapeutic approach. In establishing the RNA-based approach, a number of important steps in the process were examined including, optimisation of electroporation conditions, amount of RNA required for optimal stimulation, time from transfection to the presentation of peptides and T-cell activation, as well as the importance of maturation before or after electroporation. The optimised RNA-based transfection approach was examined on a tumour model using the prostate TAA, PSMA as functional read-out which proved to be unsuccessful due to the low-affinity of the PSMA-specific CTL clone generated. From this study, the expression pattern of claudin-4 within prostate tissue and functional data obtained indicated that claudin-4 may play an important role in tumour dissemination and that it may be a potential therapeutic target in prostate cancer. Furthermore, investigation into the use of an immunotherapeutic strategy using RNAencoded antigens to induce a DC-mediated T-cell response has revealed promising results, however, it requires further investigation using a functional tumour model.

 
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Created: Fri, 21 Nov 2008, 15:36:21 EST