Abstract
Prostate cancer (PCa) is the most widely diagnosed male cancer in the Western World and while low- and intermediate-risk PCa patients have a variety of treatment options, metastatic patients are limited to androgen deprivation therapy (ADT). This treatment paradigm has been in place for 75 years due to the unique role of androgens in promoting growth of prostatic epithelial cells via the transcription factor androgen receptor (AR) and downstream signaling pathways. Within 2 to 3 years of ADT, disease recurs—at which time, patients are considered to have castration-recurrent PCa (CR-PCa). A universal mechanism by which PCa becomes resistant to ADT has yet to be discovered. In this review article, we discuss underlying molecular mechanisms by which PCa evades ADT. Several major resistance pathways center on androgen signaling, including intratumoral and adrenal androgen production, AR-overexpression and amplification, expression of AR mutants, and constitutively-active AR splice variants. Other ADT resistance mechanisms, including activation of glucocorticoid receptor and impairment of DNA repair pathways are also discussed. New therapies have been approved for treatment of CR-PCa, but increase median survival by only 2-8 months. We discuss possible mechanisms of resistance to these new ADT agents. Finally, the practicality of the application of “precision oncology” to this continuing challenge of therapy resistance in metastatic or CR-PCa is examined. Empirical validation and clinical-based evidence are definitely needed to prove the superiority of “precision” treatment in providing a more targeted approach and curative therapies over the existing practices that are based on biological “cause-and-effect” relationship.
Highlights
Distant metastasesIt is important to note that persistent issues with the Gleason system, despite multiple rounds of revisions, have induced the urological pathology community to introduce a new Prostate cancer (PCa) grading system in 2015 [19, 20]
Prostate cancer (PCa) is the most common male cancer in the Americas, Caribbean, Western and Northern Europe, Australia, New Zealand, and several countries in sub-Saharan Africa [1]
The primary mechanism by which testosterone and dihydrotestosterone (DHT) promote PCa formation and growth is by activating androgen receptor (AR), a transcription factor to be discussed in following sections
Summary
It is important to note that persistent issues with the Gleason system, despite multiple rounds of revisions, have induced the urological pathology community to introduce a new PCa grading system in 2015 [19, 20]. This new classification still makes use of the Gleason system, but groups Gleason scores into Grade Groups 1-5 that better reflect prognosis and simplifies diagnosis for patients; future PCa diagnoses will include both Gleason score and Grade Group [19, 20]. Since all basic and clinical research studies examined in this article pre-date this change, only Gleason score will be discussed
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