Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects

Abstract

Androgen receptor (AR) signaling is a critical pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. However, over time, most tumors become resistant to ADT. The view of castration-resistant prostate cancer (CRPC) has changed dramatically in the last several years. Progress in understanding the disease biology and mechanisms of castration resistance led to significant advancements and to paradigm shift in the treatment. Accumulating evidence showed that prostate cancers develop adaptive mechanisms for maintaining AR signaling to allow for survival and further evolution. The aim of this review is to summarize molecular mechanisms of castration resistance and provide an update in the development of novel agents and strategies to more effectively target the AR signaling pathway.

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer

“…Even though treatment options for CRPC have been expanded in recent years, patients will eventually succumb to metastatic disease, supporting the need for new therapeutics for resistant disease (50). In this study, we provide evidence that, in addition to decreasing testosterone production, the AR antagonist activity jci.org Volume 127 Number 6 June 2017…”

“…Abiraterone exposure can also be enhanced by up to 17-fold when taken with a high-fat meal, and at these levels, the drug would be expected to occupy the WT-AR and the commonly occurring AR mutants (53). Furthermore, it is important to remember that, since abiraterone and other CYP17 inhibitors are extremely effective at lowering serum testosterone levels (undetectable levels of <1 ng/ dl after 8 days of abiraterone treatment), it is unlikely that the AR in tumors will be exposed to androgens as in our in vitro assays, thereby effectively lowering the IC 50 in patients and providing a 30-36). However, the extent to which AR antagonism influences the clinical efficacy of CYP17 inhibitors has not been elucidated.…”

“…AR overexpression has emerged as one of the dominant mechanisms underlying resistance to androgen-ablative therapies in prostate cancer (50). Indeed, the ability of enzalutamide to inhibit AR signaling in the context of increased receptor expression was a key factor in its development and distinguishes it from earlier-generation AR antagonists (11).…”

“…Using this approach, we determined that the CYP17 inhibitors seviteronel, galeterone, abiraterone, and ketoconazole displaced [ 3 H]-R1881 (a synthetic AR agonist) from the receptor, displaying IC 50 values of 4.86 × 10 -6 , 5.46 × 10 -7 , 7.60 × 10 -6 , and 1.76 × 10 -4 , respectively, while orteronel did not bind the receptor ( Figure 1B). In comparison, the benchmark antiandrogens enzalutamide, bicalutamide, and hydroxyflutamide effectively displaced [ 3 H]-R1881, with IC 50 values of 4.21 × 10 -7 , 1.31 × 10 -6 , and 2.07 × 10 -7 .…”

Endostatin: A novel inhibitor of androgen receptor function in prostate cancer

“…Although the current therapies using androgen deprivation and antiandrogens show transient tumor regression, the tumor relapse to castration-refractory metastatic stage remains a big challenge (1). The molecular basis of continued AR function in castration-resistant PCa (CRPC) has shifted the paradigm in our understanding of androgen-independent mechanisms, leading to therapeutic strategies directly targeting the receptor (2,3). Despite modest improvements in AR-targeted therapies, tumor relapse ensues with up-regulated AR expression and transcriptional activation of downstream AR-target genes (4,5).…”