©TheCanadian Journal ofUrology™: International Supplement, April 2014
9
TilkiANDEvans
Furthermore, in theevaluationofsecond linehormonal
therapies,patientswere includedwhohadone toup to
sixdifferent treatmentsbeforeenrollment in the same
study.
19
Scher et al presented a classification scheme
basedonhormonesensitivity including the following
three categories: 1) Hormone-naive patients who
show a decrease in tumor proliferation if androgens
are withdrawn or antiandrogens are administered
(physiologic levels of androgens in the blood).
2) Androgen-independent and hormone-sensitive
patientswithdecrease inproliferation in response to
other hormonal manipulations as mentioned above
(castration levels of testosterone). 3) Hormone-
independent (androgen-independent and hormone-
insensitive) patientswho are insensitive tohormonal
manipulations (castration levels of testosterone).
19
Extent of prostate cancer has not been included in
these definitions, while the later introduced clinical
states model of prostate cancer did differ castration
resistancebasedon risingPSAfromdifferent statesof
castration resistancebasedon clinicalmetastases.
20,21
Extensiveresearch inthepastdecadehasuncovered
several underlying mechanisms by which prostate
tumor cells become resistant to hormone therapy
(as discussed below) and led to new definitions for
prostate cancer progression despite castration levels
of testosterone.
Testosterone levels of < 20 ng/dL after surgical
castrationhavebeenmeasuredusingchemiluminescent
technology and suggested as a cut point to define
castration.
22,23
Previous toclinicalapprovalof thisnew
technique for testosteronemeasurement, a castration
cut off of 50ng/dLwasused.
23
Given that the terms androgen-independent and
hormone-refractorydonot reflect thepossibility thata
patientmayrespond toalternativehormone therapies
anddespite itswideuse, the term castration resistant
prostate cancer has emergedand establishedasmore
accurate.
According to the Canadian Urological Association
castrationresistantprostatecancer isdefinedbydisease
progressiondespite androgendeprivation therapy and
may present as either a continuous rise in serum PSA
levels, the progression of pre-existing disease, and/
or the appearance of newmetastases.
24
Similarly, the
AmericanUrologicalAssociationguidelinesdefineCRPC
as a rising PSA level and/or radiographic evidence of
prostate cancerprogressiondespitemedical or surgical
castration.
25
TheProstateCancerClinicalTrialsWorking
Group 2 (PCWG2) defines PSAonly failure as a rising
PSAthat isgreater than2ng/mLhigher than thenadir.
Therisehas tobeat least25%overnadirandconfirmed
byasecondPSAat least 3weeks later.
25,26
Summary of the latest understanding of the
biology of the androgen and androgen receptor
axis in the development of CRPC
Prostate cancer growth and survival depend on
androgenswhichregulatetheratioofcellsproliferating
to thosedying.
15
Testosterone is themain circulating
androgen, of which 90% is secreted by the testes.
Onlya small fraction (3%) of testosterone isunbound
and functionally active, while most of it is bound
to sex-hormone-binding globulin or albumin. After
entry of free testosterone through the cellmembrane
into the cytoplasm via diffusion, it is converted
to dihydrotestosterone (DHT) by the enzyme
5
α
-reductase.
15
The AR is a member of the nuclear
receptor superfamily and acts as a ligand-inducible
transcription factor. It consists of a polymorphic
N-terminal domain, a central DNA-binding domain,
a small hinge region, and a C-terminal ligand-
bindingdomain.
27,28
TheARgene is locatedon theX
chromosome and therefore is single-copy in males,
which allows for the phenotypic manifestation of
mutations without the influence of a wild-type
codominantallele.
28
DHThasafive-foldhigheraffinity
for theAR than testosterone.
The unligandedAR associates with a heat shock
protein 90 (HSP90) chaperone complex in the
cytoplasm and undergoes proteasome-mediated
degradation in the absenceof ligand.
29
Androgen binding to AR results in dissociation
of the AR-HSP-complex, homo-dimerization, and
nuclear translocation. Subsequently the AR dimer
binds to androgen response elements (ARE) in the
promoter regionsof targetgenesand recruitscofactors
for regulationof theexpressionof androgen-regulated
genes.
15,27,30,31
Other signal transduction pathways
which involve TGF, IL-6, and IGF-I, can also enhance
AR activity via phosphorylation of AR and/or AR
coregulators.
31
Approaches forADT, as discussed in detail in the
following articles of this supplement, are inhibition
of luteinizing hormone (LH) or luteinizing hormone
releasing hormone (LHRH), ablation of androgen
sources, antiandrogens and inhibition of androgen
synthesis. All of these therapeutic approaches have
in common that they reduce AR activation through
reducing levels of androgen or blockingAR binding.
Therefore AR is believed to remain active in CRPC
and to be critical in the development of CRPC.
29
Differentandrogenresistancemechanismsexist,which
enable castration resistance. Molecular mechanisms
which have been described to play an important
role in CRPC are summarized in Table 1.
15,29,31,32
These include androgen and AR dependent
