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Early
In Development: A Novel Gene Therapy For Prostate Cancer
(July 2007)
We should wish success
to Dr. Garen and his research team at Yale as they continue to pursue
their daunting and pioneering project aimed at seducing cancer cells to
provide the means for their own suicide. And although success in
applying this therapy to humans may be far off, or even not achievable,
it is intriguing just to know what they are attempting - a little
glimpse into the sophistication of therapies to come.
Dr. Garen, a professor
of molecular biophysics and biochemistry, initially presented his
strategy in a 2001 article in the Proc Nat Acad Sci, "Targeting
tissue factor on tumor vascular endothelium cells and tumor cells for
immunotherapy in mouse models of prostate cancer."
The research is premised on the observation, made early
on by Judah Folkman, that the neovasculature called forth by a
developing tumor mass is significantly different from normal blood
vessels, and as such displays a uniquely different array of endothelial
antigens. The target antigen in this case is a transmembrane receptor,
"tissue factor (TF)", also displayed on cancer cells. Dr. Garen has
synthesized a novel gene that codes for an antibody-like immunoglobulin
(he named it "Icon") that exhibits strong affinity for TF. When the
Icon/TF complex is affixed to the endothelial surface a host cytolytic
immune response kills the cells bearing the TF/Icon. Although direct IV
administration of Icon carried by a viral vector was an option, Dr.
Garen instead chose to encapsulate the synthetic gene in liposomal
nanoparticles. This is a move to safety since other studies have been
showing that the introduction of viral vectors can occasionally promote
oncogenic transformation of the target cells. In information released by
Yale, Dr. Garen was quoted: "The advantage of nanoparticles is that they
do not reproduce, are not immunogenic, and are easier to produce than
adenoviral vectors. The nanoparticles will have a tag [not the "Icon"]
on their outside that binds to tumor blood vessels."
After IV
administration the gene package is engulfed into the tumor cells which
display the target antigen, TF, and is then incorporated into nuclear
DNA, instructing the cells themselves to make the Icon molecules. Once
the Icon antibody is synthesized by the tumor cells, and after entering
the circulation, the Icon molecules home to TF antigens on metastatic
tumor cells and their vascular endothelium causing cell destruction.
Early work found no harm to non-TF bearing cells.
Earlier tests that
employed an adenoviral delivery vector resulted in long-term regression
of transplants of human prostate cancer into mice. Continuing work by
Dr. Garen's team, supported by the Competitive Awards Program (2006) of
the Prostate Foundation, will attempt to extend these observations now
using liposomal nanoparticles to deliver the synthetic gene to animal
models implanted with human metastatic prostate cancer. Let's hope Icon
is a success.
[I appreciate Dr. Alexander Steven's bringing this
material to my attention.]
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