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Pippione et al. Steroidogenic enzymes in prostate cancer

A B

Figure 18: (A) Compound 77, analogue of flufenamic acid; (B) metabolism of abiraterone to D4A [170]

activity [18] , were treated with D4A, abiraterone studies, but although able to extend overall survival
or enzalutamide respectively and cultured in the rates, it rarely has curative power. The lack of long-
presence of [3H]AD (the preferred natural substrate lasting therapeutic effects of abiraterone and ADT may
of SRD5A1) [18] . D4A (10 mmol/L) almost completely in part be linked with androgen-independent pathways
blocked conversion of AD to 5α-androstanedione and and crosstalk to signal transduction pathways and in
other 5a-reduced androgens, whereas abiraterone part to mutations to the AR [172] . An ever-increasing
and enzalutamide had no detectable effect, even at a number of studies over the past decade have
concentration of 100 mmol/L. Abiraterone has been provided insight into prostate cancer biology and it is
reported to have modest affinity for AR, particularly becoming apparent that new chemotypes and new
in the presence of mutations in the ligand-binding drug combination strategies are required to target
domain [171] . To determine how conversion from the heterogeneous prostate microenvironment more
abiraterone to the 3-keto structure of D4A affects drug effectively. Accordingly, future drug discovery should be
affinity for AR, Li et al. [170] performed a competition focussed on multi-targeting agents that inhibit several
assay. The affinity of D4A for mutant (expressed in steps in the biosynthetic steroidogenic pathway, or
LNCaP) and wild- type (expressed in LAPC4) AR is degrader drugs that eradicate the AR (normal or
greater than that of abiraterone and comparable to mutated) to prevent it fuelling PCa growth. Whereas
that of enzalutamide, and greater than bicalutamide. the former requires multifactorial drug design and
D4A also has more potent anti-tumour activity against appropriate multifunctional in vitro models, the latter
xenograft tumours than abiraterone. These findings may be a strategy to be implemented in the clinic within
suggest that direct treatment with D4A potentially could a shorter timeframe. In parallel efforts, an attractive
be more clinically effective than abiraterone treatment. route to better therapeutic outcomes is to conduct
clinical trials that explore the possibility of using certain
CONCLUSION types of drugs at a much earlier disease state. Indeed,
this is the thinking behind the STAMPEDE trial, which
Inter-patient heterogeneity and distinct patterns of tests a number of additional therapies, given alongside
abnormal expression and regulation of steroidogenic first-line ADT and is discussed by Malcolm Mason
enzymes contribute to PCa patient relapse. As in another review “Getting better at treating prostate
discussed in this review, the many enzymes involved cancer: what clinicians should want from scientists”
in the steroidogenic pathway provide obstacles and in this themed prostate cancer issue. PCa patients
opportunities for researchers engaged in developing who have suffered relapse with bone metastasis
better drugs. Currently, hormone therapy remains currently have poor overall survival rates, with only
first choice for patients with advanced PCa, either as bisphosphonates available for palliative treatment.
alone or in combination with chemotherapy. Androgen- Obstacles in obtaining bone biopsies have halted our
dependent and independent production is central to understanding of how we can effectively treat PCa
fuelling PCa growth, and the biosynthetic steroidogenic patients suffering from bone metastases. Generally, the
pathway plays a vital role in the former. Great progress PCa microenvironment is known to be under oxidative
in PCa biology and drug design have enabled effective stress and indeed this might have a significant impact
therapies to be used clinically, while several promising on how steroidogenic enzymes respond within the
preclinical strategies are underway. Newer drugs such bone microenvironment. Evidence points to the intra-
as abiraterone have performed well in several clinical tumoural synthesis of T and DHT is minimal, yet high

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