©TheCanadian Journal ofUrology™: International Supplement, April 2014
11
TilkiANDEvans
CRPC samples and increased expression of androgen
synthesis enzymes have been shown that tumor cells
are involved in androgen synthesis and thus inAR
reactivation.
29
Montgomery et al evaluated androgen
levelsand transcriptsencodingsteroidogenicenzymes
in benign prostate tissue, untreated primary prostate
cancer,metastasisfrompatientswithcastrationresistant
prostatecancer,andxenograftsderivedfromcastration
resistant metastases.
74
They showed evidence that
castration resistant metastatic prostate cancers may
adapttolowsystemictestosteronelevelsbymaintaining
intratumoral androgens through modulation of
enzymes involved in intracrine steroidogenesis and
androgen catabolism.
74
Locke and colleagues used
the LNCaP xenograft model and showed that tumor
androgens increase during CRPC progression in
correlation to PSAup-regulation.
75
Furthermore, the
authors demonstrated that all enzymes necessary for
androgen synthesis are expressed in prostate cancer
with some of them being up-regulated during CRPC
progression.
The mechanisms driving the development of
castration resistance likely vary among patients.
Recently,persistentARsignalingactivationhasreceived
much attention, leading to the identification of novel
therapeutic targets.
ProstatecancercanacquireresistancetoADTthrough
multiple mechanisms. Despite treatment of CRPC
with new effective therapeutics such as enzalutamide
and abiraterone acetate, all patients will eventually
progress.
5,7
Resistancemechanismsevolveagainstmost
ARantagonistsovertime,andthus, itremainsavaluable
goaltodevelopothertypesoftherapytargetingtheARor
moleculesthatarespecificallyrequiredforAR-regulated
transcriptional programs. Combinedandpersonalized
treatment strategies and different treatment sequences
arebeingevaluated to improve therapyof thisdisease.
Conclusions
Prostate cancer becomes castration resistant through
numerous pathways, including androgen and AR
dependent mechanisms as well as androgen/ligand
andAR independent pathways. Therefore the terms
androgen-insensitive or hormone-refractory should
be avoided and replaced by the term castration
resistant. Recent advances in understanding
molecular mechanisms of castration resistance have
led to development of novel CRPC therapeutics.
Nevertheless, CRPC remains an incurable disease.
Further understanding of the pathways involved in
castration resistancewill set thebasis fordevelopment
of therapies to increase survival in thesepatients.
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Disclosure
Dr.DeryaTilki hasnopotential conflict of interest.
Dr.ChristopherP.EvansreceivedhonorariafromJanssen,
Medivation, Astellas and has ownership interest in
Oncogenex.
