Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches

Abstract

Prostate cancer is the second-leading cause of cancer-related mortality in men in Western societies. Androgen receptor (AR) signaling is a critical survival pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. Although a majority of patients initially respond to ADT, most will eventually develop castrate resistance, defined as disease progression despite serum testosterone levels of <20 ng/dl. The recent discovery that AR signaling persists during systemic castration via intratumoral production of androgens led to the development of novel anti-androgen therapies including abiraterone acetate and enzalutamide. Although these agents effectively palliate symptoms and prolong life, metastatic castration-resistant prostate cancer remains incurable. An increased understanding of the mechanisms that underlie the pathogenesis of castrate resistance is therefore needed to develop novel therapeutic approaches for this disease. The aim of this review is to summarize the current literature on the biology and treatment of castrate-resistant prostate cancer.

Figure 1. Androgen deprivation therapy initiates alterations in gene expression profiles in prostate cancer cells

Androgen deprivation therapy results in recalibration of prostate cancer tissue androgen levels that leads to alterations in androgen receptor (AR)-driven gene expression that may contribute to castrate-resistant prostate cancer. AR variants (ARVs) may contribute to altered gene expression.

Figure 2. Stimulation of aerobic glycolysis in the development of castrate-resistant prostate cancer

Stimulation of PI3K/Akt signaling, driven in part by Cav-1-LRP6 signaling may lead to elevated levels of glycolytic enzymes and increased aerobic glycolysis in castrate-resistant prostate cancer.