Martin Gleave

Prostate Cancer (PCa) is the most common male cancer and the second leading cause ofcancer‐related deaths in North America. While many gains have been made in early detectionand treatment of localized PCa, many men still die of the metastatic disease. Androgen ablationtherapy remains the most effective therapy for patients with advanced disease. While ~80% ofpatients respond initially to this treatment, most patients progress to Castrate ResistantProstate Cancer (CRPC) stage. Current literature indicates that CRPC tumours are not uniformlyhormone refractory and may remain sensitive to therapies directed against the AR axis.Therefore, several new classes of AR‐targeting agents are now in clinical development,including more potent AR antagonists (MDV3100) and inhibitors of steroidogenesis(abiraterone). Although enthusiasm for this approach remains high, prostate tumourheterogeneity and the inevitable development of resistance dictates a critical need to betterunderstand the mechanisms of resistance in which AR remain active.In the current doctoral thesis role of heat shock protein (Hsp) 27 and Lyn tyrosine kinasein regulation of AR protein expression was investigated. The central hypothesis is that increasedexpression and activity of Hsp27 and Lyn kinase stabilizes and activates AR protein and leads toprostate cancer progression through promoting prostate cancer cell survival.Three specific objectives were accomplished in this thesis. First, the relationshipbetween Hsp27 and AR was studied. To this end, it was demonstrated that expression and activity of Hsp27 via a nongenomic mechanism regulates AR protein stability, shuttling andtranscriptional activity. In the next step, the underlying molecular mechanisms through whichLyn tyrosine kinase regulates AR activity in the castrated environment was investigated. Theexperiments demonstrated that Lyn kinase regulates AR protein expression and transcriptionalactivity and that it plays a key role in PCa progression to the castrated resistant stage. Finally, anovel role for Lyn kinase in Epidermal Growth Factor‐mediated (EGF‐mediated) AR activity wasdefined.The results obtained in this thesis defined new pathways involved in regulation of ARprotein stability and justified further investigation of Hsp27 and Lyn kinase as therapeutictargets for CRPC.

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