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Pippione et al. Steroidogenic enzymes in prostate cancer

CO-ADMINISTRATION OF INHIBITORS AND One of the first bifunctional non-steroidal small
ANTAGONISTS TARGETING THE AR AXIS molecules studied by Chen et al. [164] as therapeutic
leads for CRPC was an N-(aryl)amino-benzoate
inhibitor (77, Figure 18). The authors exploited the
Androgen biosynthesis prevention and AR signalling observation that some flufenamic acid analogues
inhibition, should in principle produce blockade of with AKR1C3 inhibitory activity also acted as AR
the AR axis. As these pathways are implicated in the antagonists [165] and subsequently synthesised a
progression of CRPC, these concurrent therapeutic second generation of AKR1C3 inhibitors in which
actions should both reduce the incidence of resistance
and increase therapeutic efficacy. Such a potential the key features were the inclusion of an additional
powerful combination strategy could replace the ring on the phenylamino ring. The derivative
current PCa treatment paradigm of sequentially adding 3-[(4-nitronaphthalen-1-yl)amino] benzoic acid
agents at the time of disease progression. Many drug (77, Figure 18A) retained nanomolar potency and
combinations targeting the AR axis are described selective inhibition of AKR1C3 but also acted as an
in literature. Unfortunately, the use of dutasteride in AR antagonist. It inhibited 5a-dihydrotestosterone-
combination with bicalutamide for advanced PCa has stimulated AR reporter gene activity with an IC 50 =
not been as successful. Dutasteride plus bicalutamide 4.7 µmol/L and produced a concentration-dependent
in patients with progressive non-metastatic PCa reduction in AR levels in PCa cells. The in vitro
did not delay further progression compared to only and cell-based effects of compound 77 makes it a
bicalutamide [157] while dutasteride in combination with promising lead for the development of dual acting
abiraterone as well as enzalutamide is currently in a agent for CRPC.
phase II clinical trial where the outcome is pending at
the time of writing [158] . Recently Liu et al. [159] showed As mentioned above, the CYP17A1 inhibitor
overexpression of AKR1C3 to confer resistance galeterone not only inhibits the enzyme but is also a
to enzalutamide. Furthermore, the combination of competitive AR antagonist and causes degradation of
[153,166-168]
indomethacin, an AKR1C3 inhibitor, and enzalutamide the AR and its variants AR-V7 and Arv567es .
resulted in significant inhibition of enzalutamide- Furthermore, galeterone also impaired AR binding
resistant tumour growth. These results suggested to DNA and selectively up-regulated degradation of
[122,123]
that AKR1C3 activation is a critical resistance the mutated T878A AR protein . For its multi-
mechanism associated with enzalutamide resistance. funtional activity, three different clinical studies have
Accordingly, the dual targeting of intracrine androgens been initiated with galeterone. A phase I clinical trial
and AKR1C3 promises to overcome enzalutamide has been completed, while a phase II clinical trial
resistance and improve survival of advanced PCa (ARMOR2) is still ongoing in CRPCa patients. A phase
patients. Subsequently, the same research group III clinical trial (ARMOR3-V7) has started recruiting
reported that treatment of abiraterone-resistant CRPCa patients that specifically express AR-V7.
cells with indomethacin overcomes resistance and Unfortunately ARMOR3-SV was terminated as it failed
enhances abiraterone therapy both in vitro and in vivo to meet its primary endpoint of demonstrating an
by reducing the levels of intracrine androgens and improvement in radiographic progression-free survival
diminishing AR transcriptional activity [160] . Furthermore, (rPFS) for galeterone versus enzalutamide in AR-V7
[169]
these studies provide preclinical proof-of-principle for positive mCRPC .
starting clinical trials focussed on investigating the
combination of using indomethacin with enzalutamide, Another interesting polyfunctional drug is D4A,
[170]
or with abiraterone for advanced PCa [69,161] . a metabolite of abiraterone. Li et al. recently
showed that abiraterone is converted to D4A in mice
BIFUNCTIONAL INHIBITORS AND and patients with PCa [Figure 18B]. D4A inhibits
CYP17A1, HSD3B and SRD5A, which are required
ANTAGONISTS TARGETING THE AR AXIS for DHT synthesis. In particular, D4A is approximately
10-fold more potent than abiraterone at blocking the
Despite the highly significant therapeutic relevance conversion of [3H]DHEA to AD by 3β-HSD in LNCaP
of combination therapies, potential advantages of a and VCaP cells.
targeted therapy based on a single drug that modulates
the activity of multiple targets over combination D4A and abiraterone similarly block conversion of [3H]
therapy are: (1) a more predictable pharmacokinetic pregnenolone to DHEA by CYP17A1, as shown by a
profile; (2) a lower probability of developing target- study in cells expressing CYP17A1 [170] . To determine
based resistance [162] ; (3) a superior safety profile; and the effect of D4A on endogenously expressed SRD5A,
(4) a minimised risk of adverse effects [162,163] . LAPC4 cells, which exhibit robust SRD5A enzymatic

Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 12, 2017 353