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Study raises questions about Prostate Cancer
therapies targeting IGF-1
Newswise — Therapies under development to
treat prostate cancer by inhibiting the
ability of insulin-like growth factor
(IGF-1) to activate its target receptor
could have unexpected results especially if
a major tumor suppressor gene – p53 – is
already compromised, according to new
research by investigators at Fred Hutchinson
Cancer Research Center.
IGF-1 is a polypeptide hormone that can
influence growth, differentiation and
survival of cells expressing the type 1
receptor (IGF-1R).
Past
clinical, epidemiological and experimental
studies have strongly implicated IGF-1 as a
contributing factor in the natural history
of prostate cancer.
However, very little has been done to prove
absolutely that the expression or activation
of the IGF-1 signaling pathway at
physiologically relevant levels is
sufficient to cause a healthy prostate cell
to become a cancer cell.
Norman
Greenberg, Ph.D., and colleagues conducted a
pair of experiments by manipulating gene
expression directly in the epithelial
compartment of the mouse prostate gland to
better understand the role of IGF-1R. In
contrast to studies that correlated elevated
levels of IGF-1 with the risk of developing
prostate cancer, Greenberg’s research showed
that eliminating IGF-1R expression in an
otherwise normal mouse prostate caused the
cells to proliferate and become hyperplastic.
Although persistent loss of IGF-1R
expression ultimately induced cell stasis
and death, both of these processes are
regulated by the tumor suppressor gene p53
that is commonly mutated in human prostate
cancers.
Hence
the researchers hypothesized that tumors
with compromised p53 might not respond
predictably to therapies targeting IGF1
signaling.
To
test their reasoning they conducted a second
experiment by crossing mice carrying the
prostate-specific IGF-1R knockout alleles
with transgenic mice that develop
spontaneous prostate cancer when p53 and
select other genes are compromised.
The
results were as predicted: Prostate
epithelial-specific deletion of IGF-1R
facilitated the emergence of aggressive
prostate cancer in the
genetically-engineered tumor prone mice.
Published in the May 1 edition of Cancer
Research, the study supports a critical
role for IGF-1R signaling in prostate tumor
development and identifies an important
IGF-1R-dependent growth control mechanism,
according to the authors.
Title
of the paper is “Conditional deletion of
insulin-like growth factor-1 receptor in
prostate epithelium.”
“If
our predictions hold true, tumor cells with
intact p53 may show the best response to
therapy targeting the IGF-1R signal, however
when p53 is not functioning normally,
response to this therapy may not be as
expected,” said Greenberg, the study’s
corresponding author and a member of the
Hutchinson Center’s Clinical Research
Division.
Greenberg’s message to clinicians who
administer IGF-R1 therapy: “We’re all hoping
for good results but let’s proceed with
caution.”
A
search of the database for clinical trials
registered with the National Cancer
Institute found 18 trials in process that
use therapies to inhibit IGF-R1.
None
of them include a tumor’s p53 status as a
criterion for recruiting research
participants, said Greenberg.
In
addition to lead author Brent Sutherland,
Ph. D., of the Hutchinson Center,
contributing research also came from
scientists at Baylor College of Medicine in
Houston, Texas, the Center for Cancer and
Stem Cell Biology at Texas A&M University
and the Institut National de la Sante et de
la Recherche Medicale in Paris, France.
The
study was funded by the National Cancer
Institute, the Prostate Cancer Foundation
and Phi Beta Psi.
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
www.fhcrc.org.
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