The categorization of
prostate cancers that are progressing after
castration as '
hormone-refractory' evolved from the clinical observation that surgical or medical
castration (i.e.
androgen ablation
therapy; AAT) is not curative and, despite an initial response, virtually all
tumors eventually regrow. Successful AAT is contingent on the dependence of
prostate cancer cells for
androgen signaling through an intracellular mediator, the
androgen receptor (AR) for survival. Current preclinical and clinical data imply that the AR is expressed and continues to mediate
androgen signaling after failure of AAT.
As AAT does not completely eliminate circulating
androgens, sufficient concentrations of
dihydrotestosterone may accumulate in
tumor cells to maintain AR signaling, especially in the context of upregulated receptor levels or increased sensitivity of the AR for activation. In addition,
ligands of non-testicular origin or
ligand-independent activation can contribute to continued AR signaling. In many cases, therefore, from the perspective of the AR, a '
hormone-refractory' classification after failure of AAT is inappropriate. Classifying prostate
tumors that progress after AAT as '
castration-resistant' may be more relevant. Clinical responses to second- and third-line hormonal
therapies suggest that the mechanisms of AR activation are in part a function of previously administered AAT. Accordingly, the increasing trend to utilize AAT earlier in the course of the clinical disease may have a greater influence on the genotype and phenotype of the resistant
tumor. In this article, we detail strategies to inhibit the growth of
prostate cancer cells that specifically target the AR in addition to those practiced traditionally that indirectly target the receptor by reducing the amount of circulating
ligand. We propose that treatment regimes combining AAT with direct AR targeting strategies may provide a more complete blockade of
androgen signaling, thereby preventing or significantly delaying the emergence of treatment-resistant disease.