Androgen receptor (AR) signaling remains the major oncogenic pathway in prostate cancer (PCa). Androgen-deprivation therapy (ADT) is the principle treatment for locally advanced and metastatic disease. However, a significant number of patients acquire treatment resistance leading to castration resistant prostate cancer (CRPC). Epigenetics, the study of heritable and reversible changes in gene expression without alterations in DNA sequences, is a crucial regulatory step in AR signaling. We and others, recently described the technological advance Chem-seq, a method to identify the interaction between a drug and the genome. This has permitted better understanding of the underlying regulatory mechanisms of AR during carcinogenesis and revealed the importance of epigenetic modifiers. In screening for new epigenomic modifiying drugs, we identified SD-70, and found that this demethylase inhibitor is effective in CRPC cells in combination with current therapies. The aim of this review is to explore the role of epigenetic modifications as biomarkers for detection, prognosis, and risk evaluation of PCa. Furthermore, we also provide an update of the recent findings on the epigenetic key processes (DNA methylation, chromatin modifications and alterations in noncoding RNA profiles) involved in AR expression and their possible role as therapeutic targets.

Advancements in research have added several new therapies for castration-resistant prostate cancer (CRPC), greatly augmenting our ability to treat patients. However, CRPC remains an incurable disease due to the development of therapeutic resistance and the existence of cross-resistance between available therapies. Understanding the interplay between different treatments will lead to improved sequencing and the creation of combinations that overcome resistance and prolong survival. Whether there exists cross-resistance between docetaxel and the next-generation taxane cabazitaxel is poorly understood. In this study, we use C4-2B and DU145 derived docetaxel-resistant cell lines to test response to cabazitaxel. Our results demonstrate that docetaxel resistance confers cross-resistance to cabazitaxel. We show that increased ABCB1 expression is responsible for cross-resistance to cabazitaxel and that inhibition of ABCB1 function through the small-molecule inhibitor elacridar resensitizes taxane-resistant cells to treatment. In addition, the antiandrogens bicalutamide and enzalutamide, previously demonstrated to be able to resensitize taxane-resistant cells to docetaxel through inhibition of ABCB1 ATPase activity, are also able to resensitize resistant cells to cabazitaxel treatment. Finally, we show that resensitization using an antiandrogen is far more effective in combination with cabazitaxel than docetaxel. Collectively, these results address key concerns in the field, including that of cross-resistance between taxanes and highlighting a mechanism of cabazitaxel resistance involving ABCB1. Furthermore, these preclinical studies suggest the potential in using combinations of antiandrogens with cabazitaxel for increased effect in treating advanced CRPC. Mol Cancer Ther; 16(10); 2257-66. ©2017 AACR.

Activation of the androgen receptor (AR) and its splice variants is linked to advanced prostate cancer and drives resistance to antiandrogens. The roles of AR and AR variants in the development of resistance to androgen deprivation therapy (ADT) and bicalutamide treatment, however, are still incompletely understood. To determine whether AR variants play a role in bicalutamide resistance, we developed bicalutamide-resistant LNCaP cells (LNCaP-BicR) and found that these resistant cells express significantly increased levels of AR variants, particularly AR-V7, both at the mRNA and protein levels. Exogenous expression of AR-V7 in bicalutamide-sensitive LNCaP cells confers resistance to bicalutamide treatment. Knockdown of AR-V7 in bicalutamide- and enzalutamide-resistant CWR22Rv1, enzalutamide-resistant C4-2B (C4-2B MDVR), and LNCaP-BicR cells reversed bicalutamide resistance. Niclosamide, a potent inhibitor of AR variants, significantly enhanced bicalutamide treatment. Niclosamide and bicalutamide combination treatment not only suppressed AR and AR variants expression and inhibited their recruitment to the PSA promoter, but also significantly induced apoptosis in bicalutamide- and enzalutamide-resistant CWR22Rv1 and C4-2B MDVR cells. In addition, combination of niclosamide with bicalutamide inhibited the growth of enzalutamide-resistant tumors. In summary, our results demonstrate that AR variants, particularly AR-V7, drive bicalutamide resistance and that targeting AR-V7 with niclosamide can resensitize bicalutamide-resistant cells to bicalutamide treatment. Furthermore, combination of niclosamide with bicalutamide inhibits enzalutamide resistant tumor growth, suggesting that the combination of niclosamide and bicalutamide could be a potential cost-effective strategy to treat advanced prostate cancer in patients, including those who fail to respond to enzalutamide therapy. Mol Cancer Ther; 16(8); 1521-30. ©2017 AACR.

Current treatments for castration resistant prostate cancer (CRPC) largely fall into two classes: androgen receptor (AR)-targeted therapies such as the next-generation antiandrogen therapies (NGAT), enzalutamide and abiraterone, and taxanes such as docetaxel and cabazitaxel. Despite improvements in outcomes, patients still succumb to the disease due to the development of resistance. Further complicating the situation is lack of a well-defined treatment sequence and potential for cross-resistance between therapies. We have developed several models representing CRPC with acquired therapeutic resistance. Here, we utilized these models to assess putative cross-resistance between treatments. We find that resistance to enzalutamide induces resistance to abiraterone and vice versa, but resistance to neither alters sensitivity to taxanes. Acquired resistance to docetaxel induces cross-resistance to cabazitaxel but not to enzalutamide or abiraterone. Correlating responses with known mechanisms of resistance indicates that AR variants are associated with resistance to NGATs, whereas the membrane efflux protein ABCB1 is associated with taxane resistance. Mechanistic studies show that AR variant-7 (AR-v7) is involved in NGAT resistance but not resistance to taxanes. Our findings suggest the existence of intra cross-resistance within a drug class (i.e., within NGATs or within taxanes), whereas inter cross-resistance between drug classes does not develop. Furthermore, our data suggest that resistance mechanisms differ between drug classes. These results may have clinical implications by showing that treatments of one class can be sequenced with those of another, but caution should be taken when sequencing similar classed drugs. In addition, the development and use of biomarkers indicating resistance will improve patient stratification for treatment. Mol Cancer Ther; 17(10); 2197-205. ©2018 AACR.