Findings suggest androgen production occurs within metastatic prostate
tumors
SEATTLE, June 2 /PRNewswire/ -- For the past 70 years the treatment of
choice for advanced, metastatic prostate cancer has been
androgen-deprivation therapy. That is, the suppression of circulating
testosterone -- the hormone that fuels prostate-cancer growth -- via
surgical castration (orchiectomy) or medical castration with
testosterone-blocking drugs. While such therapy buys time for patients, it
is not a cure, as inevitably the cancer becomes resistant to the androgen
deprivation and continues to grow.
A team of researchers led by Peter Nelson, M.D., and Elahe (pronounced
EL-ah-hay) Mostaghel, M.D., Ph.D., of Fred Hutchinson Cancer Research
Center; and R. Bruce Montgomery, M.D., and Paul Lange, M.D., of the
University of Washington School of Medicine, in collaboration with other
colleagues at UW and Oregon Health Sciences University, has uncovered what
may be the key to understanding how prostate tumors eventually become
resistant to androgen-deprivation therapy.
"We found that despite the suppression of circulating androgen levels
to very low or castrate levels, metastatic prostate tumors are themselves
able to maintain significant levels of testosterone, which fuels the growth
of the cancer," said Mostaghel, a clinical-research associate in Nelson's
laboratory, which is based in the Human Biology Division of the Hutchinson
Center.
The researchers found that testosterone levels were four times higher
in metastatic tumors from castrate men (collected immediately after death
via rapid autopsy) than in benign and cancerous prostate tissue in men with
normal circulating androgen levels (collected at the time of prostate
surgery).
This finding, reported in the June 1 issue of Cancer Research, could
lead to the development of better drugs to treat metastatic disease --
cancer that has spread beyond the prostate to distant sites throughout the
body, such as bone, lymph nodes and internal organs.
"So far we've targeted systemic, or circulating, androgens in men with
advanced prostate cancer," Mostaghel said. "What these findings suggest is
that we really need to target the metastatic prostate-tumor tissue itself
as the source of tumor androgens."
In addition to measuring androgen levels in distant tumor sites, the
researchers analyzed gene-expression patterns in the metastatic tissue to
confirm the presence of genetic pathways that control testosterone
production. The researchers indeed found within the metastatic tissue the
genetic transcripts necessary for making the proteins that produce
testosterone and other androgen hormones.
"We not only found that metastatic-tumor tissues have high enough
androgen levels within them to support continued growth of the tumor cells,
but also a critically important reason behind why those androgens are there
-- the discovery that the gene pathways for synthesizing androgens from
cholesterol appear to be present in the distant tumor sites. This finding
will allow us to start honing in on the specific source of those androgens
and how we can eliminate them," Mostaghel said. "As we develop new drug
targets, we will need to focus on enzymes that seem to be active in the
tumor tissue itself. This offers a new way of looking at hormone
suppression. In addition to systemic suppression, it suggests we also need
to target hormone suppression much more specifically, inside the tumor
itself." Doing so could improve treatment for patients with all stages of
prostate cancer, she said, from men with metastatic disease to men with
high-risk, localized tumors in which there is concern that small amounts of
cancer may have escaped the prostate.
Mostaghel and colleagues feel the most promising drug targets will be
inhibitors of CYP17 enzymes, which disrupt the conversion of progesterone
to testosterone precursors, as well as inhibitors of enzymes that perform
subsequent steps in testosterone production: AKR1C3 and 17BHSD3.
For the study, the researchers examined soft-tissue prostate-cancer
metastases obtained from eight medically or surgically castrated men via
the University of Washington rapid-autopsy program, one of a handful of
such programs in the nation. For control purposes, the researchers also
examined benign and cancerous prostate tissue from eight men who underwent
radical prostatectomy for early-stage, localized prostate cancer, and
prostate tissue from two men whose prostates were removed for reasons
unrelated to prostate cancer.
The researchers also examined metastatic human prostate-cancer cells,
obtained from androgen-deprived men, which had been engrafted and allowed
to grow in both castrated and non-castrated mice, a process called
xenografting.
Androgen levels in the xenograft tumors in the castrated mice, which
had no circulating androgen, were actually higher than in the xenograft
tumors in the mice that had not been castrated. The researchers found a
particularly striking difference in levels of DHT. "We found DHT levels to
be twice as high in the castrated mice," Mostaghel said. "That tells us
that the tumor is making testosterone and hanging on to it somehow and is
further evidence that metastatic tissue has the capacity to make its own
testosterone."
Each year, approximately 200,000 U.S. men are diagnosed with prostate
cancer. While the majority of cases are early-stage, localized disease --
due in large part to the widespread use of PSA, or prostate-specific
antigen screening -- an estimated 50 percent of patients diagnosed and
treated for clinically localized prostate cancer will progress to more
advanced disease, which kills an estimated 30,000 American men annually.
Funding sources for this research included the National Institutes of
Health, the Department of Defense and the Prostate Cancer Foundation.
At Fred Hutchinson Cancer Research Center, our interdisciplinary teams
of world-renowned scientists and humanitarians work together to prevent,
diagnose and treat cancer, HIV/AIDS and other diseases. Our researchers,
including three Nobel laureates, bring a relentless pursuit and passion for
health, knowledge and hope to their work and to the world. For more
information, please visit fhcrc.org.
CONTACT:
Kristen Woodward
206-667-5095
kwoodwar@fhcrc.org
SOURCE Fred Hutchinson Cancer Research Center
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Related links:
http://www.fhcrc.org
CONTACT:
Kristen Woodward of Fred Hutchinson Cancer
Research Center, +1-206-667-5095, kwoodwar@fhcrc.org
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