The 5[alpha]-Androstanedione Pathway to Dihydrotestosterone in Castration-Resistant Prostate Cancer

The androgen axis is central to the progression and treatment of prostate cancer. Essential components of this axis require the expression of the androgen receptor (AR) and the generation of endogenous AR agonists. The androgen signaling pathway is intimately involved from tumor initiation and invasion, to the development of metastatic disease. Translocation of the androgen-controlled TMPRSS2 regulatory region proximal to a member of the ETS-family oncogenes occurs in the transition between high-grade prostatic intraepithelial neoplasia and invasive prostate cancer, driving oncogene expression. ¹ The requirement for expression of these oncogenes, elicited by the androgen axis, continues to very late and resistant states of disease. ² Therefore, the mechanisms that regulate the androgen axis, from the generation of ligand, to AR expression, to the response of AR-regulated genes, all represent steps that are potential points of intervention for the development of new pharmacologic therapies. A precise understanding of this pathway is required for further advances in the treatment of prostate cancer.

GONADAL TESTOSTERONE DEPRIVATION

Physiological serum concentrations of total testosterone (T) are generally greater than 300 ng/dL (10.4 nmol/L). ³ In prostatic tissue, T is converted by steroid-5[alpha]-reductase (SRD5A) to 5[alpha]-dihydrotestosterone (DHT). T is capable of binding AR in the absence of metabolism to DHT, but the latter is several fold more potent and is the major androgen bound to AR in the prostate cell nucleus. ^4,5 Although 2 isoenzymes exist, in the prostate expression of SRD5A2 is greater than that of SRD5A1. ⁶ In prostatic tissue, SRD5A enzymatic activity results in DHT concentrations that are several fold higher than T, and this ratio is reversed upon treatment with pharmacologic blockade of SRD5A. ^7,8 The effect of gonadal testosterone deprivation is therefore likely due in large part to the depletion of intratumoral DHT. However, despite 94% reductions in serum T with medical castration, intraprostatic T and DHT are reduced by only 70% and 80%, respectively. ⁹ The apparent availability of precursors for the synthesis of residual intraprostatic androgens with medical castration provides a clue as to the mechanisms of resistance to depletion of gonadal T. ¹⁰ Nonetheless, responses to gonadal T depletion therapy occur in the majority of cases, although the response in the metastatic setting is nearly always temporary. ¹¹

CASTRATION-RESISTANT PROSTATE CANCER

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