Extinguishing the AR axis

The androgen dependence of prostate cancer on testosterone was first observed as early as 1941 when the effect of castration on androgen levels in prostate cancer was studied [17]. This lead to the introduction of androgen deprivation therapy and the generation of the castrate state where serum levels of testosterone are reduced to <50ng/dl or 1.7nmol/l. This treatment is initially effective in 80-90% of patients and results in PSA or radiological responses and clinical improvement in the patient's symptoms. Eventually, the patient's cancer progresses despite serum testosterone levels continuing to be low. The current term used to describe this state is 'castrate resistant prostate cancer' which has replaced the misleading term 'hormone-refractory prostate cancer'. CRPC more accurately describes the ongoing dependence of the cancer on AR signaling despite low measureable testosterone levels.

Ligand independent AR signaling is thought to occur in the majority of CRPC tumours via activation of oncogenes such as ERBB2 or H-ras and through MAP kinase signaling [18, 19]. A small proportion of CRPC tumours will also harbour amplifications or point mutations in the ligand-binding domain of the androgen receptor gene leading to altered responsiveness to ligands [20]. A third mechanism of action bypasses androgen receptor in favour of an alternative signaling pathway [21].

The evidence for ongoing androgen sensitivity is also strengthened by the observation of up regulation of AR protein levels in hormone resistant versus hormone sensitive paired xenografts [21] as well as in patient tumour samples [22, 23]. Maintained intra-tumoural levels of testosterone and dihydrotestosterone are also observed despite castrate serum androgen levels [24].

In addition to testicular androgen production, extragonadal sites of androgen synthesis also contribute to testosterone levels. These de novo adrenal and intra-tumoural pathways utilize the 17a-hydroxylase and C17, 20-lyase activity of the CYP17A1 enzyme involved in the steroid biosynthesis pathway. The importance of this pathway was initially clinically exploited with the use of ketoconazole, a weak reversible inhibitor of CYP17. Anti-tumour activity was demonstrated with a PSA response rate of 20-62% in phase II trials and a median duration of response of 3-7 months [25]. However its use was associated with significant toxicity and up to 20% of patients discontinued treatment. This toxicity profile has not been observed with the more potent CYP17 inhibitor abiraterone acetate. This agent has successfully reawakened interest in further manipulation of the AR axis in CRPC patients. After successful phase I and II clinical trial development [26, 27] randomized double blind placebo controlled phase III trials of abiraterone plus prednisolone versus placebo plus prednisolone in chemotherapy naïve and post docetaxel patients were conducted. Results in post docetaxel patients revealed a statistically significant increase in median overall survival of 3.9 months in favour of abiraterone as well as improvements in time to PSA progression, radiological PFS and PSA response rate [28]. More recent results from the interim analysis of chemotherapy naïve patients have also shown significant activity in favour of abiraterone with the interim data monitoring committee recommending unblinding and crossover for patients receiving prednisone alone [29]. Abiraterone was also well tolerated with the predominant toxicities being hypertension, hypokalaemia and fluid retention. These are the expected consequences of the mineralocorticoid excess resulting from the accumulation of precursors upstream of CYP17. These have subsequently been managed with the concomitant use of steroids or the mineralocorticoid antagonist eplerenone.

Orteronel (or TAK 700, Takeda Pharmaceuticals) is another 17,20 lyase inhibitor which has also advanced to phase III CRPC trials after successful phase I and II development [30, 31]. This inhibitor is now in phase III trials as a single agent in asymptomatic CRPC patients and in patients with a rising PSA but no detectable metastatic disease as well as in phase I/II trials in a number of prostate cancer settings including in combination with docetaxel in meta-static CRPC patients.

In addition to steroid biosynthesis inhibitors, further manipulation of the AR axis in castrate patients has been demonstrated using MDV3100 or enzalutamide. First generation anti-an-drogens such as bicalutamide, flutamide and nilutamide competitively inhibit the AR ligand binding domain. This response is often transient as castration resistance develops which may in part be a consequence of the partial agonist activity of this class [21]. These observations led to the rational design of enzalutamide, an orally available anti-androgen with superior AR binding compared to bicalutamide, and no AR agonist activity in bicalutamide-resistant and AR-over expressing cell lines [32]. A phase I/II study of enzalutamide in 140 post-chemotherapy metastatic CRPC patients demonstrated a PSA response rate of 56% (78/140 patients), soft tissue responses in 22% (13/59 patients), and a median time to progression of 47 weeks. enzalutamide was well tolerated with the most common grade 3 or 4 adverse events being fatigue that resolved with a dose reduction [33]. This activity was confirmed in the multicentre double blind placebo controlled phase III AFFIRM trial comparing enzalutamide against placebo. This trial of 1199 docetaxel pre-treated patients was also stopped early due to a 4.8 months overall survival benefit for enzalutamide compared to placebo with all subgroups benefiting [34].

Other agents in development that manipulate the androgen receptor axis are shown in table 1. In addition to agents intrinsic to the androgen receptor pathway, inhibitors of chaperone proteins may also be important targets. Histone deacetylases (HDAC) are enzymes which remove acetyl groups from proteins and in so doing modulate the proteinprotein interactions of co-activators associated with AR binding. HDAC enzymes are over expressed in certain solid tumours including prostate cancer, where high expression levels are associated with poor outcome [35]. HDAC over expression in prostate cancers is also often co-existent with genetic rearrangements in the ETS (E-twenty six) gene family. These genetic alterations have been found in up to 70% of prostate cancers and may interact with HDAC's already known to be upstream regulators and downstream transducers of the ETS transcription factors family [36]. The preclinical rationale for HDAC inhibition in prostate cancer has led to early phase clinical development of several HDAC inhibitors. Phase I/II studies of panobinostat both as a single agent and in combination with docetaxel confirmed the safety of this approach [37]. In the single arm study, all patients developed progressive disease despite evidence of acetylated histones in peripheral blood mononuclear cells, however 5 out of 8 (63%) patients in the combination study had a > 50% reduction in PSA value. At present a study in combination with bicaluta-mide in CRPC patients is recruiting. However trials involving single agent vorinostat (an HDAC6 inhibitor known to acetylate tubulin and stabilize microtubules) have been terminated early due to excess toxicity with no significant activity [38, 39].

The other major group of agents that are involved in post-translational modification of the AR axis are heat shock proteins. These are proteins that ensure the maintenance of oncogenic protein homeostasis in the presence of stress factors such as hypoxia or acidot-ic conditions. Heat shock protein 90 (HSP 90) is an ATP-dependent multi-chaperone complex implicated in the function of the AR. The AR is stabilized by the interaction with HSP 90 that allows it to interact with androgens [40]. Pre-clinical models have shown HSP 90 inhibition leads to decreased AR expression and function and a phase I trial of 17-AAG both as a single agent and in combination with cytotoxic chemotherapy demonstrated drug safety [41]. The subsequent phase II study however failed to reach its primary endpoint and was terminated [42]. Significant toxicity was observed with the 17-AAG analogue retaspmycin (or IPI-504) [43] although clinical development of the second generation HSP90 inhibitor STA9090 has confirmed safety in phase I trials and is proceeding [44]. Studies are planned to determine whether the newer HSP90 agents can hit target and decrease activity with a suitable toxicity profile or whether the therapeutic window is too narrow for safe use of these agents.

In addition, small interfering RNA's (siRNA's) are a class of double stranded RNA molecules that are now known to exist as important gene regulatory factors in both plant and animal systems. Selective targeting of the androgen receptor by siRNA molecules may further silence the AR signaling pathway in prostate cancer. This may be made viable by nanoparti-cle technology being able to facilitate use of otherwise undeliverable agents. The development of these agents is currently hampered by the need for safe systemic delivery of these agents without the off target and immune stimulation problems encountered with other nucleic acid medicines such as plasmid DNA and anti-sense oligonucleotide [45].

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