The hormone deprivation therapy that prostate cancer
patients often take gives them only a
temporary fix, with tumors usually regaining their hold
within a couple of years. Now, researchers at
Johns Hopkins have discovered critical differences in the
hormone receptors on prostate cancer cells
in patients who no longer respond to this therapy. The
findings, reported in the Jan. 1 issue of Cancer
Research, could lead to a way to track disease
progression, as well as to new targets to fight prostate
cancer.
Prostate cancer cells rely on androgens, male hormones
that include testosterone, to survive
and grow. Since 1941, doctors have taken advantage of this
dependency to battle prostate cancer by
depriving patients of androgens, either by castration or
chemical methods. For most patients, this
hormone deprivation therapy causes tumors to shrink,
sometimes dramatically. However, it's never a
cure; tumors eventually regrow into a stronger form,
becoming resistant to this and other forms of
treatment.
Seeking the reason why this therapy eventually fails,
Jun Luo, an assistant professor at Johns
Hopkins' James Buchanan
Brady Urological Institute, and his colleagues at the
Johns Hopkins
University School of Medicine and the University of
Washington and Puget Sound VA Medical Center
looked to a key player: the androgen receptors on prostate
cancer cells.
Using a large database, the researchers searched for
variations of the nucleic acid RNA that
prostate cells use to create androgen receptors, eventually
identifying seven RNA sequences
different from the "normal" androgen receptor already known
to scientists. When they looked for
these sequences in cells isolated from 124 prostate cancer
patients, they found overproduction of
these outlaw variants in prostate cancer cells taken from
patients whose disease had become resistant
to hormone deprivation therapy. One variation, AR-V7, was
also prevalent in a select group of patients
who had never taken hormone therapy but whose cancer
aggressively regrew after surgery to remove
their tumors.
To see how androgen receptors made from AR-V7 differ
from others, the researchers forced
lab-grown prostate cancer cells to produce only the AR-V7
sequence. Unlike cells with other androgen
receptors, those with only AR-V7 receptors acted as if they
were continually receiving androgens —
turning on at least 20 genes that rely on androgens for
activation — even though no androgens were
present.
The results suggest that hormone therapy might
encourage prostate cancer cells to
overproduce the AR-V7 receptors over time, leading them to
survive and grow aggressively even
without androgens, Luo said. In some patients, he added,
AR-V7 receptors might already be prevalent
even without hormone therapy, predisposing them to an
already aggressive form of prostate cancer
that won't respond as well to hormone deprivation
therapy.
"We may eventually be able to develop an assay to test
for this androgen receptor variant,
giving us a way to test which patients are good candidates
for hormone deprivation therapy and
providing a way to monitor disease progression in patients
already on this therapy," Luo said.
Examining the differences between AR-V7 and other
androgen receptor variants may also
provide researchers with new ideas to develop prostate
cancer-fighting pharmaceuticals, he said.
Other researchers who contributed to this study are
Rong Hu, Thomas A. Dunn, Shuanzeng Wei,
Sumit Isharwal, Robert W. Veltri, Elizabeth Humphreys,
Misop Han, Alan W. Partin, William B. Isaacs
and G. Steven Bova, all of the Johns Hopkins University
School of Medicine; and Robert L. Vessella, of
the University of Washington and Puget Sound VA Medical
Center.
This research was funded by a grant from the David H.
Koch Foundation.