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Where Is The Silver
Bullet When We Need It ?
It's natural for
clinicians after reading (above) about the continuing essentialness of a
functioning androgen receptor for the promotion of tumor progression in
hormone refractory prostate cancer to speculate whether the total
elimination of this receptor would be a route to successful treatment.
It is technically possible to shut down the expression of the AR gene.
The investigators in the Sawyers group did so by infecting
hormone-refractory PC cells with a virus expressing a "short hairpin
interfering RNA" against the androgen receptor gene thus effectively
canceling its expression. Researchers at Norvartis Pharma Research were
working in this direction as described in the abstract "Specific block
of androgen receptor activity by antisense oligonucleotides", Prostate
Cancer & Prostate Diseases 6(1):2003. They developed a short strand of
complementary nucleotides that bound to the mRNA product of the AR gene
and cut off the expression pathway. The absence of AR prevented the
activation of the many genes that promote prostate cancer growth such as
the peptide growth factors Her2/neu, epithelial growth factor,
insulin-like growth factor, IL-6, etc, and, of course, the steroid
growth factor, Dihydrotestosterone. Unfortunately, they have decided not
to pursue this research.
Possibly
expectations for success by AR elimination are too great. Developments
in treatment of prostate's sister endocrine malignancy, breast cancer,
are always instructive, in this case as they relate to the new breast
cancer drug, fulvestrant ("Faslodex"). Fulvestrant downregulates the
estrogen and progesterone receptors. Although this agent does not
interrupt the production of the estrogen receptor (which has a very
analogous function to the AR in prostate cancer), fulvestrant
continuously destroys the estrogen receptor as it is continuously
produced, thus shutting down signaling via this pathway. With what
success? Modest. When fulvestrant is used to treat breast cancer after
it has escaped from primary hormone intervention (a situation akin to
progression of PC to hormone refractory disease post Lupron) the
clinical response rate was 23% and the median time to disease
progression was 8 or so months. Perhaps a drug directed at the androgen
receptor would produce only a similarly modest benefit, that is to say,
useful, but not a silver bullet!
Bottom Line:
We clinicians and researchers are up against a clever opponent. Lycopene
And Selenium in Prostate Cancer Article
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