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R EVI E W A R T IC L E Targeting the androgen receptor signalling axis in castration-resistant prostate cancer (CRPC) BJUI BJU INTERNATIONAL Che-Kai Tsao, Matthew D. Galsky, Alexander C. Small, Tiffany Yee and William K. Oh Division of Hematology and Medical Oncology, The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA Accepted for publication 31 May 2012 What’s known on the subject? and What does the study add? Castration resistance has been appreciated for decades, and several mechanisms theorising on this effect have been proposed. A rich pipeline of novel agents, including abiraterone and MDV3100, have provided proof of principle that novel agents targeting the AR signalling pathway with superior selectivity and activity than predecessors have yielded significant clinical benefit for patients with metastatic castration-resistant prostate cancer. Our review provides an update in the development of several novel agents targeting the AR signalling pathway now in clinical testing, as well as review novel therapies in development with distinct mechanisms of action showing promising preclinical activity. • Despite undergoing local therapy with curative intent, 20–30% of patients with prostate cancer will ultimately development metastatic disease, leading to morbidity and mortality. • Androgen-deprivation therapy (ADT) for men with metastatic prostate cancer results in transient clinical benefit, but ultimately, cancers progress despite castrate levels of serum testosterone, a clinical state classically referred to as ‘hormone refractory’ disease. • In this review, we examine mechanisms of resistance to ADT that have redefined our understanding of the more appropriately termed ‘castration resistant’ disease, and have paved the way for a new generation of therapeutics targeting the androgen signalling axis in advanced prostate cancer. KEYWORDS INTRODUCTION prostate cancer, castration resistance, androgen deprivation, novel endocrine therapy, hormone refractory, androgen receptor Prostate cancer is the most common non-skin cancer in men in the Western world [1]. While widespread PSA screening has significantly increased prostate cancer detection, about one-third of men treated with definitive local therapy will have disease recurrence, while another subset will present with advanced disease at the time of initial diagnosis [2]. Prostate cancer growth and progression is stimulated by androgens, acting through the androgen receptor (AR). Circulating androgen levels are predominately regulated through the hypothalamic-pituitary-adrenal-gonadal axis and androgen-deprivation therapy (ADT) results in temporary disease regression in most patients. However, this approach eventually fails, as tumours develop mechanisms to grow despite chemical or surgical castration and inevitably leading to significant morbidity and mortality. THE NORMAL PROSTATE AND THE AR ‘Prostate cancer growth and progression is stimulated by androgens, acting through the androgen receptor’ 1580 The prostate is responsible for producing most of the fluid in the seminal plasma volume of men’s ejaculate. Binding of © 2 0 1 2 B J U I N T E R N A T I O N A L | 11 0 , 1 5 8 0 – 1 5 8 8 | doi:10.1111/j.1464-410X.2012.11445.x TARGETING THE AR SIGNALLING AXIS IN CRPC FIG. 1. AR signalling and mechanisms of castration resistance. Testes MECHANISMS OF CASTRATION RESISTANCE Steroidogenesis Ligand Dependent Ligand Independent Adrenal gland Persistent intratumoral androgens DHT AR AR Splice Variants Autocrine Androgen Production AR AR AR AR AR Gene Amplification Tumour cell proliferation PROSTATE TUMOUR CELL AR Mutation Co-activators Co-repressors AR Proteins CYTOPLASM NUCLEUS RNA AR Epigenetic changes androgens to the AR, expressed in epithelial and stromal cells of the prostate [3], results in differentiation, metabolism, proliferation, and survival of these cells. The AR is composed of ligand-dependent intracellular transcription factors that are known to influence the development and growth of prostate cancer. Mouse models show that androgens are required at every step of prostate development [4], as a nonfunctional AR results in a testicular feminisation-like syndrome with absence of the prostate [5]. While androgens are produced by both the Leydig cells of the testes (testosterone: 90–95%) and adrenal gland (5-dehydroepiandrosterone [DHEA] and androstenedione: 5–10%), conversion to dihydrotestosterone (DHT) by 5α-reductase occurs in the prostate. The AR has three main regions: the N-terminal domain (NTD), which contains the activation function; a central DNA binding domain; and a COOH-terminal domain (CTD), which contains the ligandbinding region. The AR is a nuclear hormone receptor normally bound in a complex with multiple chaperones (heat-shock proteins, hsps). Upon androgen binding, AR changes its conformation, leading to nuclear © 2012 BJU INTERNATIONAL translocation and subsequent dimerization with androgen response elements in the promoter and enhancer regions of target genes [6]. Through cytoplasmic signalling [7–9] and recruitment of co-activator proteins [10], target gene transcription is enhanced, which leads to cellular proliferation. PROSTATE CANCER: THE ROLE OF ANDROGEN AND AR clones exist before the initiation of ADT is not known [11]. With ADT, selective pressure selects for androgen-resistant clones preferentially to proliferate. Additional molecular changes may cause resistant populations of cells to become dominant, leading to state known as castrationresistant prostate cancer (CRPC). Several mechanisms of castration resistance have been proposed, classified broadly as either ligand-dependent or ligand-independent pathways (Fig. 1). The clinical management of patients with CRPC is challenging, as several of these mechanisms may be involved simultaneously in any given patient. LIGAND-DEPENDENT MECHANISMS OF CASTRATION RESISTANCE Persistent androgens despite castration Despite castration, alterations in the multi-step processing of androgen synthesis and transport can provide high enough concentrations of androgens in the tumour microenvironment to drive tumour growth and progression. The clinical efficacy of secondary hormonal agents targeting the androgen–AR axis after progression despite castration has provided a proof of principle Since the work of Huggins and Hodges demonstrated regression of metastatic prostate cancer with surgical ‘AR is a nuclear hormone receptor normally castration in the bound in a complex with multiple chaperones’ 1940s, manoeuvres to deplete that residual androgens can stimulate androgens have remained the standard continued tumour proliferation. Both first-line treatment for metastatic disease. adrenal and intra-tumoral androgens have However, this strategy ultimately fails as been recognised to play an essential tumours develop mechanisms to grow role in the development of CRPC [12]. despite low levels of circulating androgens. Whether resistant prostate cancer ‘Both adrenal and intra-tumoral androgens have been recognised to play an essential role in the development of CRPC’ 1581 TSAO ET AL. Polymorphisms in androgen conversion and transportation have also been associated with outcomes in CRPC [13]. Furthermore, a recent study showed that DHT synthesis may bypass testosterone in driving castration resistance [14]. Taken together, these findings highlight the multiple steps in the pathway of androgen synthesis and transport that can be commandeered by tumour cells to maintain adequate levels of androgens in the microenvironment to support growth. The adrenal glands have long been recognised as a potential source of androgen production despite surgical or chemical castration. Early attempts to maximize adrenal androgen blockade via adrenalectomy had limited efficacy [15]. Subsequently, the antifungal ketoconazole, a cytochrome P450 and 17,20-lyase inhibitor blocking the synthesis and degradation of adrenal steroids, was used to treat men with CRPC confirming the importance of extra-testicular sources of androgen production in subsets of patients [16]. The clinical activity of ketoconazole also provided the conceptual, and molecular, framework for the development of more selective adrenal androgen inhibitors. More recently, the importance of intratumoral androgen production has emerged. Several studies showed that despite castrate levels of serum testosterone, residual levels of testosterone remain sufficiently elevated in the prostate cancer microenvironment, suggesting an ‘autocrine’ pathway of androgen production may play an important role in developing castration resistance [12]. Selective stress from castration causes prostate cancer to up-regulate enzymes responsible for de novo steroidogenesis and adrenal steroid conversion and fuel intra-prostatic androgen [17–21]. AR gene amplification ‘epigenetics 1582 Compared with hormone-sensitive prostate cancer cells, up to one-third of CRPC tumours harbour AR gene may play an important role in the amplification [22–24]. Despite development of CRPC’ castration, AR hypersensitivity to low levels of androgens results in continued tumour proliferation [23,25]. In addition, heightened AR sensitivity to DHT is associated with increased AR expression, stability, and nuclear localisation in CRPC cells [26]. Therapeutic use of AR blockade may also lead to AR over-expression and hypersensitivity [27]. LIGAND-INDEPENDENT MECHANISMS OF CASTRATION RESISTANCE Conventional hormonal therapy is ineffective when tumours grow in a truly androgen independent manner, thus posing a major clinical challenge, particularly as more potent and selective androgen biosynthesis inhibitors and AR blockers emerge. Several mechanisms have been hypothesised to play important roles in the development of castration resistance including genetic variations, epigenetic changes, and alteration of transcriptional and translational regulation, leading to tumour proliferation without ligand binding. AR mutations Although AR mutations are uncommon in CRPC, it has been speculated that AR is activated by several hormones, including progesterone, oestrogen, adrenal androgens and metabolic by-products of DHT [28–30]. In addition, mutant ARs may also bind AR antagonists [31,32], as well as corticosteroids [33]. The promiscuous nature of the mutant AR may be responsible for the anti-androgen withdrawal syndrome, whereby patients with progressive disease on an anti-androgen experience a transient disease remission simply by discontinuing the anti-androgen. In these cases, the drug was presumably exerting agonistic, rather than antagonistic functions [34]. Epigenetic modification Recent work has shown that epigenetics may play an important role in the development of CRPC [35]. Preclinical models have shown that post-translational modifications, e.g. histone modification and DNA methylation, can lead to castration resistance [36]. DNA hypermethylation down-regulates the AR suppressor binding complex leading to increased AR expression [37], while DNA hypomethylation during androgen deprivation increases AR signalling in CRPC [38]. Adaptor/scaffolding protein © 2012 BJU INTERNATIONAL TARGETING THE AR SIGNALLING AXIS IN CRPC TABLE 1 Mechanisms of novel AR-targeted agents in clinical development Mechanism of castration resistance Ligand dependent Residual androgens (adrenal + intratumoral) AR binding (gene amplification) Ligand independent Constitutively active AR splice variants Epigenetic modifications Drug action Novel drugs CYP17 inhibition 17,20-lyase inhibitor Analogue of 3β-androstanediol (d-cholesterol -x- > d-pregnenolone) CYP17 inhibition + AR antagonist AR antagonist + AR translocation inhibitor Analogue of 3β-androstanediol (AR antagonist) CYP17 inhibition + AR antagonist Targets AR NTD Abiraterone TAK-700 Apoptone TOK-001 MDV3100/ARN509 Apoptone TOK-001 EPI-001 AR antagonist + AR translocation inhibitor Anti-AR mRNA HDACi Hypomethylating agent MDV3100 EZN4176 Panobinostat Azacitidine TABLE 2 Recent and on-going Phase III clinical trials of novel agents targeting AR signalling axis Clinical Trial COU-301 COU-302 Agent Abiraterone Abiraterone No. of patients 1000 1158 Criteria Post-Docetaxel Pre-Docetaxel Primary endpoint OS OS AFFIRM PREVAIL NCT01193244 NCT00716794 MDV3100 MDV3100 TAK-700 TAK-700 1199 1680 1083 1454 Post-Docetaxel Pre-Docetaxel Post-Docetaxel Pre-Docetaxel OS OS, PFS OS, PFS OS, PFS Outcome/primary completion date Favourable OS Favourable PFS Study Un-blinded Favourable OS September, 2014 October, 2013 January, 2013 NOVEL ENDOCRINE THERAPIES PFS, progression-free survival; OS, overall survival. receptor for activated C kinase 1 (RACK1), via binding to the tyrosine kinase Src, modulates the tyrosine phosphorylation of AR, facilitating AR translocation. This process is ligand independent, resulting in up-regulation of transcriptional activity in hormonally treated prostate cancer cells [39]. AR-mediated transcriptional activation of several proliferation and apoptotic pathways is critically dependent on histone acetylation [40]. Novel therapeutic strategies targeting these post-translational modifications are now being investigated in clinical trials, although early trials of these agents have not yet shown significant clinical activity [41,42]. AR splice variants AR splice variants ARs have been hypothesised to contribute to the © 2012 BJU INTERNATIONAL the setting of castration, co-activators such as hsp27 [46,47], Her2Neu tyrosine kinase [48], bcl-2 [49], and IGF-binding protein 5 [50] are up-regulated, and associated with the development of castration resistance. Likewise, co-repressors have been described in AR regulation [51], with mechanisms such as direct sequestration by DAX-1 [42], and interruption of AR C- and N-terminal interaction by Filamin-A [52,53]. development of CRPC [43]. Under normal conditions, the androgen-AR complex will translocate into the nucleus, and regulate expression of androgen-responsive genes. However, AR splice variant isoforms are constitutively active, promoting tumour cell growth independently of ligand [44]. Recent work has shown that the AR signalling inhibitor MDV3100 inhibits the growth of prostate cancer cell lines harbouring some AR splice variants [45]. AR co-activators and co-repressors Upon binding with androgen, AR recruits co-regulatory proteins, which include chromatin-remodelling complexes and transcription machinery that leads to modulation of transcription. Several AR co-activators have been identified as major contributors to the development of CRPC. In With a better understanding of the mechanisms resulting in castration resistance, novel therapeutic agents that target residual androgen and the AR signalling axis have shown significant preclinical activity, and have rapidly entered clinical testing (Table 1). Already, Zytiga (abiraterone acetate) and Enzalutamide (MDV3100) have both been shown to improve survival in patients with CRPC (Table 2). Abiraterone acetate Abiraterone acetate, an irreversible inhibitor of cytochrome p450 complex CYP17, is an oral agent that suppresses adrenal steroid and intra-tumoral androgen synthesis. Compared with its predecessor ketoconazole, abiraterone is both more potent and selective. In a phase I study, abiraterone administered at multiple dose levels resulted in marked reductions in serum testosterone levels to <1 ng/dL, and resulted in regression 1583 TSAO ET AL. of measurable disease [54]. Because mineralocorticoids increased and resulted in related adverse events (AEs), e.g. hypertension, hypokalaemia, leg swelling, adding epleronone was effective in ameliorating these events. Responses were also seen in patients previously receiving ketoconazole in a second phase I study [55]. ‘evidence suggest that AR common in CRPC and may resistance to conventional Two phase II trials using abiraterone 1000 mg and prednisone 10 mg daily further demonstrated the favourable tolerability and clinical activity in the treatment of CRPC. In patients who were chemotherapy naïve, 67% had a PSA level decline of >50%, 37.5% of patients with measurable disease had partial amplification is response by RECIST confer therapeutic criteria, and 66% had stable disease anti-androgens’ at 6 months [56]. However, secondary mineralocorticoid excess resulted in significant hypokalaemia (88%), hypertension (40%), and fluid overload (31%), necessitating eplerenone treatment. A separate study evaluated patients with CRPC that had previously received docetaxel [57]. Even in this heavily pre-treated population, 36% of the patients had >50% PSA level declines, 18% of the patients had partial radiographic response, and the median time to PSA progression was 169 days. Importantly, with the co-administration of 10 mg oral prednisone, clinical manifestations of mineralocorticoid excess were not observed. Two large phase III randomised trials of abiraterone were initiated to evaluate two separate patient populations. COU-AA-301 randomised 1195 patients in a 2:1 ratio to treatment with abiraterone and prednisone in patients with CRPC who previously received docetaxel. The combined treatment arm showed a statistically significant overall survival benefit (14.8 vs 10.9 months, hazard ratio [HR] 0.65, P < 0.001) [58]. In addition, other clinical endpoints, including time to PSA progression (10.2 vs 6.6 months, HR 0.58, P < 0.001), radiographic progressionfree survival (5.6 vs 3.6 months, P < 0.001), and PSA response (38% vs 10%, P < 0.001), favoured the combined treatment arm. Abiraterone was associated with increased AEs, including fluid retention, hypokalaemia, hypertension, transaminitis, and cardiac 1584 dysfunction in the combined treatment arm, generally low-grade and manageable. COU-AA-302 is a double-blinded, placebocontrolled, phase III study that randomised 1088 patients with chemotherapy naïve CRPC to compare abiraterone 1000 mg and prednisone 10 mg daily vs prednisone alone. A recent press release of the interim analysis by an independent monitoring committee concluded that differences in radiographic progression-free survival, overall survival, and secondary endpoints favoured the combined treatment arm [59]. MDV3100 Several lines of evidence suggest that AR amplification is common in CRPC and may confer therapeutic resistance to conventional anti-androgens [60]. MDV3100 was developed based on preclinical activity even in the presence of AR amplification [61]. Compared with older generation non-steroidal anti-androgens, MDV3100 has greater affinity for AR, and in addition inhibits AR nuclear translocation without detectable agonist effects. In a phase I–II study, escalating doses of MDV3100 were evaluated in patients with progressive CRPC [62]. A dose of 240 mg/day was selected for further investigation, as higher doses increased the risk of seizures. In the phase II portion, administration of MDV3100 achieved PSA level declines of >50% in 56% of patients and radiographic responses in 22% of patients. Circulating tumour cell counts showed 49% (25/51) of patients converting from an unfavourable count before treatment (>5 cells/7.5 mL blood) to a favourable count after treatment (<5 cells/7.5 mL blood) [63]. Interestingly, PET imaging with 18F-fluoro-5α-DHT showed decreased androgen to AR binding, confirming the original hypothesised mechanism of action. Two randomised, placebo-controlled, phase III trials of MDV3100 have been conducted, evaluating its efficacy in patients with both pre(PREVAIL) and post-docetaxel CRPC (AFFIRM). Recently reported interim analysis of the AFFIRM trial, which randomised 1199 patients in a 1:1 ratio, showed that estimated median survival was 18.4 months for men treated with MDV3100 compared with 13.6 months for men treated with placebo (P < 0.001), with a 37% reduction in the risk of death with MDV3100 [64]. © 2012 BJU INTERNATIONAL TARGETING THE AR SIGNALLING AXIS IN CRPC TAK-700 Epigenetic therapy TAK-700 is a 17, 20-lyase inhibitor that significantly reduces adrenal and testicular androgen levels. After showing significant in vitro activity against prostate cancer cell lines, a phase I/II, dose-escalation study was initiated. TAK-700 was administered at five dose levels, with prednisone 5 mg twice daily. With additional patients treated at a dose of 400 mg twice daily, dose limiting toxicity was seen. The most common AEs were fatigue (17 patients, three grade ≥3 with 600 mg twice a day), nausea (11 patients, one grade 3), and vomiting (seven patients, two grade ≥3). Pharmacokinetic analysis showed dose proportional increases in single and multiple dose maximum plasma concentrations of the drug (Cmax) and the area under the concentration–time curve (AUC0–8h). Impressively, the median testosterone and DHEA sulphate levels decreased from 5.5 to 0.6 ng/dL and from 50.0 μg/dL to below quantifiable levels, respectively. All patients treated with ≥300 mg doses had a PSA level decrease and in patients who received at least three cycles of TAK-700 ≥300 mg, 12 (80%) had PSA level reductions of ≥50% and four (27%) had reductions of ≥90%. Given its efficacy and safety, two randomised, placebo-controlled, phase III trials have been initiated to evaluate TAK-700 with prednisone in patients with metastatic CRPC in the docetaxel-naïve and docetaxel-treated populations. Histone deacetylase inhibitors (HDACi), via Galeterone (TOK-001) is the first compound modulation of HDAC activity, have a broad to have multi-functional inhibitory activity spectrum of epigenetic activities that have on the AR signalling axis. In addition to yet to be fully defined. SAHA, also known as inhibiting CYP17, TOK-001 is also a very vorinostat, is a USA Food and Drug potent inhibitor of adrenal androgens and Administration (FDA) approved HDACi for the ‘Hypomethylating agents have also shown treatment of favourable preclinical activity in the treatment cutaneous T cell of CRPC’ lymphoma, and has shown anti-tumour activity in prostate cancer cell lines [69]. In clinical trials as ARs. A phase I, multicentre, dose-finding monotherapy, vorinostat did not exhibit study in patients with chemotherapy naïve anti-tumour activity, and was associated CRPC was published in the American Society with significant AEs in men with docetaxelof Clinical Oncology (ASCO) meeting in 2012 treated CRPC [41]. A phase I trial of [73]. Patients were enrolled in cohorts from oral panobinostat, another HDACi, with 650 to 2600 mg of TOK-001 daily, with 36 or without docetaxel, showed that the of 49 patients completing the 12-week dose limiting toxicities were neutropenia treatment course. The treatment was and dyspnea, respectively [70]. As evident generally well tolerated, with only one in cell lines, adding panobinostat to severe AE considered related to TOK-001 docetaxel showed clinical activity even in (rhabdomyolysis with acute renal failure, patients who previously progressed on with high dose statin use). Overall 22% of docetaxel, providing a suggestion that treated patients had a >50% PSA level HDACi may overcome chemotherapy decline, and an additional 26% had 30–50% resistance. A phase Ib study with i.v. PSA level declines. Consistent with lyase panobinostat with docetaxel is currently inhibition, increased corticosteroids and on-going. suppressed androgens were seen with dose escalation. Hypomethylating agents have also shown favourable preclinical activity in the ARN-509 treatment of CRPC [71]. 5-Azacitadine, an FDA-approved agent for the treatment of Like its structural analogue of MDV3100, myelodysplastic syndrome, is a potent false ARN-509 inhibits both AR nuclear substrate competitive inhibitor of ‘In addition to inhibiting CYP17, TOK-001 is methyltransferase also a very potent inhibitor of adrenal via its incorporation androgens and ARs’ into DNA and RNA during cell replication and transcription, leading to translocation and AR binding to androgen silencing of promoter genes. In mouse response elements in DNA, but with greater models, combined treatment with castration efficacy in prostate cancer cells with and azacitidine delayed time to castration over-expressed AR [74]. In a pilot phase I resistance [72]. In 36 patients with study, 30 patients with metastatic CRPC chemotherapy naïve CRPC, treatment received ARN-509 daily in nine dose with azacitidine exhibited acceptable escalating cohorts [75]. The most common treatment associated AEs (four grade grades 1–2 treatment-related AEs were 3 fatigue, two grade 3 neutropenia, fatigue (38%), nausea (29%), and pain and no grade 4 AEs) but only modest (24%), with one treatment-related grade 3 in vivo clinical activity [33]. A trial of AE (abdominal pain) at 300 mg. At 12 weeks combined therapy with docetaxel in patients of treatment, 42% of patients have had with chemo-naïve CRPC is currently ≥50% PSA level declines. An optimal underway. biological dose of 240 mg daily was selected Apoptone Apoptone, also known as HE3235, is a novel synthetic analogue of 3β-androstanediol that has shown significant preclinical activity against prostate and breast cancer [65]. In cell lines, apoptone binds to ARs, resulting in the down-regulation of Bcl-2 and increased expression of caspases. In human prostate adenocarcinoma cell lines, apoptone decreased AR expression, and in a CRPC xenograft suppressed tumour growth and tumoral androgen synthesis. Additionally, independent of CYP17 inhibition, apoptone inhibits conversion of d-cholesterol to d-pregnenolone. An on-going phase I/II study is exploring the pharmacokinetics, safety, and activity of apoptone in patients with both chemo-naïve and chemotherapy-treated metastatic CRPC [66–68]. © 2012 BJU INTERNATIONAL TOK-001 1585 TSAO ET AL. for phase II investigation, with PSA response at 12 weeks selected as the primary endpoint [76]. REFERENCES 1 EZN4176 2 EZN4176, an anti-sense oligonucleotide mRNA antagonist of AR, exhibited potent AR and tumour inhibition in both androgen dependent and independent xenograft models. Upon administration, EZN-4176 is hybridized and releases the complementary sequences of AR mRNA, thus blocking translation of the AR protein, leading to inhibition of AR-induced tumour cell growth, and promotes tumour cell apoptosis in AR over-expressing tumour cells. This therapy has now entered phase I clinical testing. EPI-001 While nearly all androgen ablative agents target the CTD and its ligand binding region, therapeutic effort against the NTD have recently begun. EPI-001, a small molecule that inhibits transactivation of the AR NTD, has been developed as a promising agent for the treatment of CRPC [77]. The unique mechanism and target of this drug escape several mechanisms of castration resistance such as gain-of-function mutations in the ligand-binding domain, or expression of constitutively active splice variants. This promising approach to targeting of the AR has yet to enter clinical trials. 3 4 5 6 7 8 9 SUMMARY For decades, treatment of CRPC has been limited, resulting in dismal outcomes for patients who failed initial hormonal treatment. However, abiraterone and MDV3100 have provided proof that despite castration resistance, more potent and selective agents targeting the androgen–AR signalling axis can be effective. A rich pipeline of novel therapeutic agents is currently in various stages of preclinical and clinical development. Continued efforts to combat mechanisms of AR resistance will be critical to improving prostate cancer outcomes in the future. 10 11 12 CONFLICT OF INTEREST 13 Dr William K. 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J Clin Oncol 2012; 30 (Suppl.): abstract TPS4697 Andersen RJ, Mawji NR, Wang J et al. Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. Cancer Cell 2010; 17: 535–46 Correspondence: William K. Oh, Mount Sinai School of Medicine, The Tisch Cancer Institute, 1 Gustave L Levy Place, New York, NY 10029, USA. e-mail: [email protected] Abbreviations: ADT, androgen-deprivation therapy; AE, adverse event; AR, androgen receptor; ASCO, American Society of Clinical Oncology; CRPC, castration-resistant prostate cancer; CTD, COOH-terminal domain; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; FDA, USA Food and Drug Administration; HDAC(i), histone deacetylase (inhibitors); hsp, heat-shock protein; NTD, N-terminal domain. © 2012 BJU INTERNATIONAL