New Study Raises Questions About Prostate Cancer Therapies Targeting Insulin Like Growth Factor Receptor

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.


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