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Title: The role of the Raf/MAP kinase pathway in the development of androgen-insensitive prostate cancer
Author: Mukherjee, Rono
ISNI:       0000 0001 3429 2716
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2005
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Prostate cancer is the second most commonly diagnosed cancer in the Western world and the second most common cause of male cancer-specific death. The development of novel therapies to treat androgen-insensitive prostate cancer (AIPC) has been hampered in the past by limited information regarding underlying molecular causes. A profound understanding of the various molecular pathways involved is crucial as specific targets are needed for molecular-based cancer therapy. Such potential targets include the type 1 receptor tyrosine kinases (EGFR and HER2) and their downstream pathways. We hypothesised that the Raf/MAP Kinase cascade to be one such pathway, based on previous gene array data from our laboratory. This revealed amplification of members of the Raf/MAP Kinase pathway along with HER2 with the development of AIPC, which suggested that the Raf/MAP Kinase pathway promoted the development of clinical AIPC. The purpose of this M.D. was to further investigate the role of this signal cascade in AIPC by determining if these previously identified genetic changes had functional consequences in terms of protein expression. The role of the Raf/MAP Kinase pathway was investigated using clinical, archival material which consisted of paired, matched histological tissue specimens obtained before commencement of androgen deprivation therapy and after the development of androgen-escape. The expression levels and activation status of Raf-1 and MAP Kinase (2 critical members of the MAP kinase cascade) were determined in these matched ASPC and AIPC tumours using immunohistochemistry. Protein expression was then correlated with time to biochemical relapse, time to death from relapse and overall survival. Correlations were also made with the type 1 tyrosine kinase receptors, EGFR and HER2 (known to activate the pathway), and the known downstream targets, AR and AP-1, in the same cohort of patients. In doing so, increased protein expression of the pathway was seen to significantly impact on patient survival. Patient tumour specimens which displayed a rise in Raf-l expression had a significant reduction in time to biochemical relapse (< 0.0005). Furthermore, rising nuclear expression of MAP Kinase was strongly associated with shortened time to death from (p=0.0255) relapse resulting in reduced overall survival (p=0068). Correlations also existed with other critical members of the pathway in vivo. Correlations were seen between type 1 receptor tyrosine kinases and members of the Raf/MAP Kinase pathway before and after the development of AIPC, whilst further significant correlations developed with the c-fos and c-jun (components of the transcription factor AP-1) with the development of AIPC. From this data, the following can be concluded. Raf-1 and MAP Kinase appear to be involved in the development of AIPC, as their expression significantly impacts on known clinical parameters - namely, time to biochemical relapse and overall survival. This indicates a potential prognostic role for the MAP Kinase cascade in AIPC. In addition, positive correlations with other proteins may indicate that a type 1-tyrosine kinase receptor/Raf-MAP Kinase /AP-1 axis forms a functional pathway which plays a role in the development of clinical AIPC. This would imply that members of the Raf/MAP Kinase pathway may act as a therapeutic target in selected patients. The data provides, for the first time, clinical evidence to support our hypothesis that the Raf/MAP Kinase pathway is utilised in AIPC and plays a role in promoting its' development and progression. Further analysis of this pathway, and its' role in AIPC using clinical material, are clearly warranted. These findings lead us to hypothesise further that expression of Raf-1 and MAP Kinase would yield useful predictive information for patients at risk of AIPC and that targeting of the type 1-tyrosine kinase receptor/Raf-MAP Kinase /AP-1 axis in this sub-group of patients may yield a novel and exciting therapeutic avenue in the future.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available