Replies to post #63212 on Biotech Values

[HobGlobulin]

RE: IGF-1 Pathway

[With cancer, there's always another wrinkle.]

http://genengnews.com/news/bnitem.aspx?name=34741901&taxid=0

>> May 1 2008, 12:50 AM EST

Study raises questions about prostate cancer therapies targeting IGF-1

Contact: Dean Forbes
[e-mail]
206-667-2896
Fred Hutchinson Cancer Research Center
SEATTLE

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, Greenbergs 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 studys corresponding author and a member of the Hutchinson Centers Clinical Research Division.

Greenbergs message to clinicians who administer IGF-R1 therapy: Were all hoping for good results but lets 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 tumors 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.

Note to reporters/editors: To obtain a copy of the study, please contact Dean Forbes, 206-667-2896 or [e-mail]

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. <<

[biophud]

Thoughts on IGFR antagonists. I'm optimistic about this class of drugs. In general it is a good sign when multiple academic and industry groups come to similar conclusions.

I think the worry about a me-to-mess can be overstated. Multiple statins coexist in the market, and in terms of biologics there are multiple TNF-alpha inhibitors (AMGN, J&J, ABT, and many more in development).

Also, there is the issue that biological are complex molecules that vary by isotype, affinity, and ability to activate ADCC.

Based on the clinical trials that I have read about, I would expect different companies to stake out specific therapeutic areas where they are not in direct competition (at least initially). IMO

biophud