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Title: Novel strategies to enhance androgen receptor-targeted therapy in prostate cancer : a molecular and pharmacological appraoach
Author: McCourt, Clare Margaret
ISNI:       0000 0004 2741 9688
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2012
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Prostate cancer is the most common cancer in men in the U.K. and the second leading cause of cancer-related death in men in the Western world. Androgen deprivation therapy (ADT), for example the anti-androgen bicalutamide, is the cornerstone treatment for prostate cancer, including advanced disease. Resistance to anti-androgens is a major impediment to the effective treatment of prostate cancer and a key contributor to the development of a castrate-resistant phenotype. Elucidating the underlying aberrant signalling pathways leading to bicalutamide resistance are necessary to design and develop novel treatment strategies that enhance the efficacy of bicalutamide and delay the emergence of castrate-resistant prostate cancer (CRPC). The chemokine IL-8 IS over-expressed in prostate cancer and has been implicated in the tumourigensis, angiogenesis and metastasis of disease. Ligand- independent activation of the AR by growth factors and chemokines is a key pathway by which prostate cancer cells can survive and flourish following ADT. We have previously reported that IL-8 can activate the AR, independent of androgen binding, leading to the downstream transcription of AR-related pro-survival and anti- apoptotic genes. In the current study, we have shown that IL-8 can induce the expression of an anti-apoptotic AR-regulated gene c-FLIP; in so doing, the regulation of c-FLIP may maintain the survival of prostate cancer cells and progression of disease. Increased expression and activity of AR co-activators is another principle pathway leading to the development of CRPC and we have shown that IL-8 can up- regulate the expression of the AR co-activator β-catenin, upstream of c-FLIP. Our data suggests that co-operation between the AR and β-catenin, following IL-8 stimulation, enhances the expression of c-FLIP. Over-expression of c-FLIP in human prostate cancer is responsible for survival and anti-apoptosis. In the current study, we have shown that molecular and pharmacological targeting of c-FLIP can enhance the efficacy of bicalutamide and is potentially an effective treatment modality for prostate cancer to delay the onset of castrate resistance. In an initial series of experiments, siRNA-mediated silencing of c-FLIP, not only resulted in apoptosis but sensitised prostate cancer cells to bicalutamide- induced apoptosis. Due to the limitations of RNAi-based therapies in the clinic; we exploited the use of several small molecules that decrease c-FLIP expression. The . HDACi droxinostat and SAHA, down-regulated c-FLIP and induced apoptosis in both the androgen-dependent cell lines tested. Additionally, pre-treatment with either HDACi sensitised cells to bicalutamide and further decreased c-FLIP expression. We extended our studies using SAHA as this HDACi has received regulatory approval for the treatment of cutaneous T cell lymphoma and clinically relevant doses were able to induce apoptosis in prostate cancer cells. The combination of SAHA and bicalutamide resulted in significant apoptosis through the down-regulation of several anti-apoptotic and pro-survival regulators. In further experiments, our findings suggest cell-specific regulation of c-FLIP in drug response relating to the relative basal activities and status of the AR and NF-KB transcription factors between 22RVl and LNCaP cells. We propose that SAHA and bicalutamide is a clinically relevant treatment strategy for the regression of 22RVl- and LNCaP- like human prostate tumours as a means to circumvent bicalutamide resistance and delay the onset of advanced CRPC. To determine the potential clinical benefit of treating prostate cancer patients with SAHA and bicalutamide, we broadened our investigations using the VCaP androgen-sensitive prostate cancer cell line, representative of castrate-resistant metastatic tumour cells that possess a hyper-activated AR. We identified that VCaP cells are intrinsically resistant to SAHA-induced apoptosis and that this may be associated with increased basal expression of c-FLIP and BCL-2 in this cell line (relative to 22RVl and LNCaP cells) and the inability of SAHA to down-regulate the expression of these anti-apoptotic proteins. Additionally, no sensitisation to bicalutamide was observed in VCaP cells and SAHA induced the transcriptional activity of the AR and NF-KB transcription factors. In summary, our findings generated using VCaP cells suggest that the combination of SAHA and bicalutamide would not be a valuable treatment modality to use in metastatic castrate-resistant patients and may cause disease progression as a result of SAHA-induced activation of transcription factors. We propose that SAHA and bicalutamide is a potentially effective treatment post-radiation or post-radical prostatectomy to delay the development of an advanced castrate-resistant phenotype.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available