Basic science of hormonal therapy for prostate cancer

Abstract

New developments in molecular and cellular biology are rapidly increasing knowledge of the mechanisms of androgen action in the prostate. Molecular profiling of recurrent cancer after androgen deprivation therapy has revealed genetic changes related to cell survival and proliferation. It is now clear that loss of the androgen receptor (AR) does not explain androgen-independent growth of a majority of recurrent cancers. Rather, overexpression, mutation, and ligand-independent activation of the AR may confer enhanced sensitivity to androgen or other growth factors. Therefore, the term "androgen-independent" is often a misnomer. This emerging concept is the basis of novel strategies to prevent or slow recurrence.

Figure 1

Events occurring in the normal prostate following androgen ablation. At T₀, the epithelium and vasculature are intact and androgen is bound to the AR of secretory epithelial cells. At T_6h after androgen depletion, the earliest observed event is degeneration of the vasculature. By T_48h, secretory epithelial cells undergo apoptosis. At later time points (T_>6d), only basal epithelial cells remain.

Figure 2

Status of the androgen receptor (AR) in recurrent, hormone-refractory prostate cancer. In a subset of cancers, AR is absent and growth is driven by AR-independent mechanisms. In the majority of cancers, however, AR is present. Amplification of AR makes cells supersensitive to low levels of androgen. Mutation may reduce ligand specificity, permitting activation of the AR by non-androgens. Activity of the wild-type AR may be driven by high levels of peptide growth factors that activate AR by ligand-independent mechanisms.