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Androgen Receptors: "Signaling
continues during androgen insensitivity." (October 2002
It is appropriate to begin this series by discussing the
androgen receptor, the kingpin of the prostate and prostate cancer. As we
all know, when we roll an apparent "strike" with an LHrH agonist, the pins
frustratingly come back up in less than three years. Why this occurs is
not fully known. To change the analogy, we don't know if one bad apple
from the start gradually spoils the bushel (clonal selection) or multiple
somewhat bad apples learn new tricks and gradually take over (adaptation).
We do know that signaling via the AR controls cell growth, survival, and
differentiation. And even in the clinical situations we call partial or
total "androgen insensitivity", prostate cancer growth and survival is
still promoted via AR signaling, albeit, by "abnormal" signals.
In the July 1st 2002 issue of Journal of Clinical Oncology, Vol.
20,3001-3015 Edward Gelmann reports comprehensively on the "Molecular
Biology of the Androgen Receptor". I'll quote what, in my opinion, is the
most relevant passage for clinicians:
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"However, after hormone
deprivation therapy, a number of AR gene alterations have been
found. These alterations lead to increased sensitivity of the
receptor to low levels of circulating androgens and to the
receptor's ability to recognize a broadened spectrum of ligands as
potent agonists of AR action. All these findings underscore the
general notion that the AR signaling pathway is usually maintained
in advanced prostate cancer that progresses after first-line
androgen ablative therapy." |
Although their exact mechanisms of
action are not known, the trio of second-line hormonal agents (Ketoconozole,
DES, Dexamethasone) may to some extent function by decreasing the adrenal
output of dehydroepiandrosterone (DHEA), which is converted into
testosterone (and then to dihydro- testosterone) and thereby further
deprive the AR of the agonist by adding to the suppression by the LHrH
agent or to the effect of prior castration.
Androgen deprivation, and also high dose anti androgen monotherapy, seem
to result in amplification of the AR gene in 25% to 30% of progressing
patients (adaptation) and paradoxically may facilitate response to
second-line hormone therapy. Androgen deprivation also seems to select for
mutations. Clinicians are familiar with the phenomenon of the
"anti-androgen withdrawal response" resulting from mutations in the region
of the ligand-binding pocket of the AR. Since the AR is located on the X
chromosome no paired allele is available to blunt the effect of the
mutation.
Once a ligand has mated with the receptor many events occur down the
signaling pathway to DNA transcription and beyond. There are co-repressors
and co-activators and DNA binding factors and transcription machinery.
"The binding of co-repressor molecules are favored when anti-androgens
[i.e., Casodex, Eulexin] occupy the ligand binding pocket" (Gelman, ibid)
To date, we have mainly focused therapeutically on the ligand binding
pocket employing agents that diminish signaling. However, in the future,
with a fuller understanding of the entire signaling chain, researchers may
be able to provide the clinician with many additional agents to target
sites further down the signaling pathway and interrupt the AR's
stimulation of growth and survival of prostate cancer cells.
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