The Utility of Combination of Prostate Specific Antigen ( Psa ) Nadir Level and Time to Psa Nadir Following Androgen Deprivation Therapy as a Reliable Prognostic Factor in Advanced Prostate Cancer

Androgen deprivation therapy (ADT) is standard systemic therapy for advanced prostate cancer (PCa), however, in some cases temporary remissions may occur and in others cancer can become castration-resistant prostate cancer (CRPC). Most of CRPC still express androgen receptor (AR) and depend on the AR for growth. Several mechanisms that enhance AR signaling in low androgen conditions have been reported. These include changes in AR expression and structure through gene amplification, mutation, and alternative splicing. Changes in steroid metabolism, coactivator and corepressor proteins, and cell signaling pathways are also important contributors to AR reactivation in CRPC. Recent studies have shown that the combination of prostate-specific antigen (PSA) nadir and time to PSA nadir (TTN) are, at least in part, early prognostic factors in advanced PCa patients with initial hormone therapy. In this review, the biology of PSA and the mechanisms for AR reactivation subsequent to ADT are summarized. In addition, we discuss the possible mechanisms responsible for the association of shorter TTN with poor prognosis of advanced PCa during ADT, and we propose appropriate ADT strategies. Central Onishi et al. (2014) Email: JSM Clin Oncol Res 2(2): 1014 (2014) 2/8 BIOLOGY OF PSA PSA is an androgen-regulated serine protease and member of the tissue kallikrein family of protease [19]. Prostate glands in human consist of a single layer of secretory epithelial cells, which are surrounded by a continuous layer of basal cells and a basement membrane. PSA is produced by secretory epithelial cells in prostate gland and is secreted directory into the lumen. A characteristic of prostate cancer is disruption of the basal cell layer and basement membrane, and this loss of normal glandular architecture results in the increase of serum PSA [20-22]. Transcription of PSA gene is regulated by androgens through the androgen receptor (AR) [23]. The AR is a steroid hormone receptor that binds as a homodimer to the specific DNA sequence, termed androgen-responsive elements (AREs). A consensus ARE is located at -156 to -170 from the transcriptional start site of the PSA gene [24]. The PSA distal enhancer is located approximately 4.2 kb upstream of the transcription start site which is a region containing single strong consensus ARE (ARE III). Furthermore, the presence of multiple additional weak non consensus AREs have demonstrated by binding studies. The cooperative binding of multiple ARs to this region likely accounts for its strong androgen-dependent activity [22,25-28]. The decrease in PSA levels after ADT is certainly resulted from tumor cell death and/or decreased expression of AR-stimulated PSA in surviving tumor cells. As a result, ADT may in some cases have greater effects on PSA production than on tumor survival. Combined castration and AR antagonist treatment results in more rapid decrease of PSA and lower PSA nadir than castration alone; however, this does not translate into a significant improvement in survival [22,29]. AR is activated by protein kinase A and/or protein kinase C pathway in the absence of androgen and the androgenindependent induction of PSA gene expression in LNCaP cells is regulated by AR-dependent pathway [30-32]. Mitogen-activated protein kinase signaling may also regulate PSA transcription in androgen-independent manner [33]. MECHANISMS OF PROGRESSION TO CRPC AFTER ANDROGEN-DEPRIVATION THERAPY Free Testosterone enters prostate cells and gets converted to dihydrotestosterone (DHT) by 5α-reductase, which in turn binds to the AR. The AR is a nuclear transcription factor that can activate and regulate the expression of several genes involved in growth and proliferation [34-36]. ADT is the standard therapy for advanced PCa patients. However patients invariably relapse with progression to become CRPC. Studies show that most of the CRPC still express AR, and AR gene amplification occurs in about one third of CRPC patients [37,38]. Thus, AR transcriptional activity and signaling may increase under an androgen-depleted condition in CRPC. Several molecular mechanisms can lead to the AR reactivation after ADT.