Molecular determinants of prostate cancer aggressiveness

Abstract

The diagnosis of prostate cancer (PCa) is still mainly based on morphological criteria but is supported by biomarker analysis, which is currently mainly performed on an immunohistochemical basis. Newly developed techniques progressively extend biomarker analyses on oncogenic driver mutations at the genomic level. Transcriptome analyses provide a new way to comprehensively analyze biomarker expression at mRNA level and offers the opportunity to identify and establish a whole set of novel biomarkers. A confirmed diagnosis enables correct therapeutic intervention and thus a reliable prognosis. The study presented in chapter I explored and estimated the number of potential biomarkers to be expected from a transcriptomic analysis of primary PCa samples. At least 250 genes that are positively associated with prognosis were identified. About 50% of the top 15 identified genes are already in the focus of PCa research, which demonstrates the good prospects of biomarker search by transcriptome analysis. The importance of biomarkers is of undeniable relevance for the early detection and clinical treatment of PCa. More precise diagnoses and prognoses based on specific biomarkers can lead to an improved patient stratification and eligibility. Chapter II explored the predictive nature of the AR splice variant “V7” expression in irradiation of PCa primary tumors. As AR-V7 expression promotes the repair of DNA double strand breaks induced by irradiation, its presence would predict a limited success of this therapeutic intervention. While AR-V7 expression is rare in primary tumors, it emerges after prolonged systemic androgen deprivation therapy, rendering the tumor successively resistant to AR inhibition. Besides AR-V7, further resistance mechanisms involving AR signaling occur upon long-term androgen-deprivation therapy (ADT). In chapter III, an analysis of <em>in vitro</em> PCa models long-term treated with different generations of antiandrogens (AAs) to mimic ADT in patients revealed AA-specific molecular adaptations that result in resistance formation. However, resistance development involving AA treatment deserves and requires a deeper molecular characterization, which will unveil treatment algorithms that render PCa diagnosis and therapy more reliable. Unravelling the complex interconnections between disease drivers, drug targets and resistance effectors will allow for the identification of specific biomarkers. Considering the multitude of opportunities that are left in this research area, novel approaches such as the investigation of novel gene signatures and the development of new treatment regimens are needed. An overall deeper understanding of the connections between mechanisms and pathways underlying distinct therapy approaches will allow for improved therapy strategies that clearly benefit PCa patients.