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Pippione et al. Steroidogenic enzymes in prostate cancer

ARs in tumour cells exposed to ADT undergo selective Unfortunately, most CRPC patients treated with AR-
alterations that result in aberrant AR reactivation, antagonist therapy will eventually develop resistance
which ultimately allows the AR pathway to remain and succumb to the disease. Mechanisms of
active despite the shortage of androgenic ligands. AR resistance to these drugs include modification of the
amplification leads to AR overexpression, which is AR, AR gain-of-function point mutations, truncated AR
[6]
present in approximately 30% of CRPCs. Mutations in isoforms and constitutively-active AR splice variants .
the AR gene occur in approximately 20% of CRPCs. Accordingly, new agents to target these alternative
Most significant AR mutations occur in the LBD, which ARs through novel mechanisms of action should lead
increase the sensitivity and decrease the specificity of to intensified research in the PCa community and lead
ligand binding [112] . Constitutively active splice variants to new drugs with clinical potential.
(AR-Vs) are detected in PCa cell lines (e.g. LNCaP95,
VCaP and 22Rv1) and in CRPC tissues. More than AR-antagonists can be classified based on their ability
20 AR-Vs have been reported, but only ARv567 to interact with different domains of the AR. Approved
and AR-V7 are considered to be clinically relevant drugs and similar structures under development show
because their levels of expression are correlated affinity for the LBD. These molecules, also named
[6]
with CRPC and poor survival rates [Figure 12] . AR- traditional AR antagonists, compete with androgens
V7, like other AR variants lacks an LBD, and via its in binding the AR and prevent formation of the AF-2
nuclear localisation binds DNA independently, without (activation function-2) hydrophobic groove inside the
androgen activation, regulating a unique set of target LBD and its interaction with co-regulators. However,
genes that facilitate mitosis in addition to the regular in some cases, the AR can still dimerise and become
nuclear, as observed with enzalutamide using confocal
androgen-dependent genes that are activated by full- micrographs [119] . Apalutamide (55, Figure 13) and
length ARs that promote disease progression [113] .
darolutamide (56, OMD-201) are two molecules under
evaluation in phase 3 clinical trials in patients with non-
As other steroid hormone receptors, also AR appear metastatic CRPC (NCT01946204 and NCT02200614,
to be regulated by epigenetic mechanisms [27] . The first respectively). Apalutamide shows high structural
evidence of epigenetic regulation of AR came from similarity to enzalutamide, but achieves the same
comparing the hypermethylation of AR promoters in therapeutic response as enzalutamide at a lower dose
AR-deficient and AR-expressing cell lines (hyper- and in a LNCaP xenograft mouse model and does not
hypomethylated, respectively) [114] . In human prostate induce AR nuclear translocation or DNA binding [120] .
cancer, a significant role of hypermethylation of AR Darolutamide is characterised by a different chemical
genes has been suggested: AR hypermethylation scaffold from its cognate antagonists, and is able to
was observed both in primary cell lines from PCa antagonise AR mutants F876L, W741L and T877A [121] .
patients (20%) and in hormone-refractory prostate
cancers (28%) [115] . Also other epigenetic mechanisms, Seviteronel (5, Figure 4), a non-steroidal CYP17A1
such as histone acethylation/deacethylation, seem to inhibitor with 17,20-lyase selectivity (see above), has
participate in the regulation of AR-driven genes [116] . been found to show AR-antagonist activity independent
of CYP17A1 enzyme inhibition, with evidence of direct
The literature is abundant with research articles and binding to the AR LBD [40] . Similarly, also galeterone
reviews concerning the development of AR-based (3, Figure 4) is a competitive AR antagonist mediated
therapy for PCa. The AR is a validated therapeutic by binding of the drug to the steroid-binding pocket
target for PCa and five molecules have already of AR and concomitantly inhibiting T biosynthesis
been approved by the FDA (cyproterone acetate through inhibition of CYP17A1 lyase activity [36] . In
50, flutamide 51, nilutamide 52, bicalutamide 53, addition, galeterone targets the LBP of mutated T878A
enzalutamide 54, Figure 13) [117] while several others AR. The authors also reported on PSA reduction in
are currently under preclinical/clinical development. LNCaP and VCaP cell lines, an effect that was partially
Among papers of considerable interest on AR, we reversed upon addition of DHT in a dose-dependent
recommend the following for further reading: the manner [122,123] .
report of Lu et al. [118] that describes the mechanism of
function of AR and its targetable domains, the review The SAR for AF-2 targeting have been extensively
[6]
by Imamura and Sadar , which focuses on AR- studied [124-126] , and X-ray structures of AR-LBD
related mechanisms of resistance and AR antagonist in complex with T (PDB: 2AM9), R-bicalutamide
therapeutic agents undergoing clinical trials, and (PDB codes: 1Z95 and 4OJB, Figure 14) or
finally the review by Martinez-Ariza and Hulme [117] , that hydroxyflutamide (PDB: 2AX6) and other ligands have
encompasses non-ligand-binding protein modulators been resolved [127] . Essentially, the compounds consist
of the AR. of three structural parts: the first part is usually an
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 12, 2017 347