Loss of the Retinoblastoma Tumor Suppressor Pushes Prostate Cancer into Lethal Stage, Say Kimmel Cancer Center Researchers
The retinoblastoma tumor suppressor
gene (Rb), long thought to protect cells against cancer development, appears to
play a very different role in prostate cancer, say scientists at the Kimmel Cancer Center at Jefferson. As reported today, disruption of this gene
now appears to be a major factor contributing to therapeutic failure.
Their study, published in the
December issue of the Journal of Clinical
Investigation, shows that loss of either the Rb gene or its protein is a
major contributor of progression to the incurable “castration resistant” stage
of the disease – cancer that no longer responds to standard androgen
deprivation therapy, and is linked to poor survival. In other tumor types, Rb
is generally viewed as a powerful tumor suppressor through its ability to block
cell division. In fact, Rb loss is associated with development of up to half of
all solid tumors, including breast and lung cancers.
The first clues that Rb was doing
something different in prostate cancer came when postdoctoral fellow Ankur
Sharma, Ph.D., and the study’s lead investigator Karen E. Knudsen, Ph.D., a
Professor of Cancer Biology, Urology, & Radiation Oncology at Jefferson Medical
College of Thomas Jefferson University, found this paradigm did not hold true
for human prostate cancers. In these
tumors, the researchers observed that Rb loss was strongly associated not with
prostate cancer development but with advanced disease that responds poorly to
therapy. Further, Dr. Knudsen and her
collaborators found that if they reduced Rb levels in human prostate cancers
grown in a dish or in a mouse, tumors did not ramp up their growth. That
suggested Rb was not acting in its canonical tumor suppressor role of
controlling cell division.
In the laboratory, the researchers
then mimicked androgen deprivation therapy, which is the mainstay of treatment
for patients whose tumors have spread beyond the prostate. “We took tumors that
still responded to androgen deprivation therapy, and suppressed Rb. All of a sudden these tumors grew,” Dr.
Knudsen says. “With Rb, tumors respond
to androgen deprivation therapy. Without Rb, they don’t.”
Androgen deprivation therapy acts
by blocking the action of the androgen receptor, and prostate cancer cells are
typically ‘addicted’ to androgen receptor action, Dr. Knudsen says. “We found that in human prostate cancers, Rb
loss allows for enhanced production of the androgen receptor. This event overwhelms androgen deprivation
therapy,” she says. “In effect, Rb serves a special role in prostate cancer by
limiting androgen receptor production, activity, and resultant tumor cell
growth. Conversely, Rb loss releases
that brake, androgen receptors are then overproduced, and the transition to
castration-resistance can ensue.”
Linking Rb loss to therapy-
resistance in prostate cancer explains a puzzle long seen in treatment clinics
– why it is that a subset of prostate tumors suddenly displays dramatically
high levels of the androgen receptor, says Dr. Knudsen. “This finding was
unexpected, as it provides some of the first evidence that tumor suppressor
genes can control progression to an incurable phase by dampening androgen
action. However, it was necessary to further
test these ideas in samples from patients who sadly failed androgen deprivation
therapy.”
The research team from the Kimmel Cancer
Center at Jefferson then worked
collaboratively with Peter Nelson, M.D., and his associates at the University of Washington
and the Fred Hutchison Cancer
Research Center,
which has expertise in analyzing tumors from patients that have failed
therapy. Together, they found loss of Rb
occurred with high frequency in the therapy resistant tumors, and corresponded
to high levels of the androgen receptor. “So what we had seen in our laboratory
and animal models of human disease studies held true in patients as well,” Dr.
Knudsen says.
The researchers say these new
findings may prove useful in a number of ways.
One is that researchers may be able
to “barcode” prostate tumors in the same way that breast cancer is molecularly
profiled, in order to help direct clinical therapy.
“Based on our data, Rb status in a
prostate tumor may tell us whether or not a patient is likely to respond to
androgen deprivation therapy,” Dr. Knudsen says. “Currently, we have no way of
knowing that.”
Multiple tests are being developed
to check for presence of the Rb gene in tumor samples or for Rb protein – in
much the same way that breast cancer screens look for the presence of estrogen
and progesterone receptors and HER2 genes, she says.
Furthermore, now that oncologists
know the molecular reasons why Rb-deficient tumors may not respond to androgen
deprivation therapy, it may be possible to design new therapies that interrupt
the pathway that leads to, or is associated with, Rb loss, says Dr. Knudsen. In
this study, the research team detailed a number of molecular players in that
pathway, and new clues in the laboratory have uncovered novel means to more
effectively treat tumors showing Rb loss.
“Based on what we’ve seen so far,
assessing Rb status in a tumor may provide a means to tailor therapeutic
intervention for better outcomes,” says Dr. Knudsen. “We are well into the next steps, and with appropriate
support, we hope to move our ideas into the clinic as quickly as possible.”
“This was a team science
initiative, wherein basic scientists and expert clinicians from the Greater
Philadelphia Prostate Cancer Working Group and beyond worked together to model
and test our hypotheses in the condition that matters most – human disease,”
Dr. Knudsen adds.
This study was funded by grants
from the National Cancer Institute, the Department of Defense Pre-doctoral
Prostate Cancer Fellowship Program, and the Prostate Cancer Foundation.
The authors declare no conflicts of
interest.
Media Only Contact:
Jackie Kozloski
Thomas Jefferson University Hospital
Phone: (215) 955-6300
Published: 11/22/2010