Jefferson Scientists Deliver Toxic Genes to Effectively Kill Pancreatic Cancer Cells
New “Suicide Gene” Delivery Approach Offers Potential for Novel Therapy
A
research team, led by investigators at the Department of Surgery at
Jefferson Medical College of Thomas Jefferson University and the Kimmel
Cancer Center at Jefferson, has achieved a substantial “kill” of
pancreatic cancer cells by using nanoparticles to successfully deliver
a deadly diphtheria toxin gene. The findings – set to be published in
the October issue of Cancer Biology & Therapy – reflect the first time this unique strategy has been tested in pancreatic cancer cells, and the success seen offers promise
for future pre-clinical animal studies, and possibly, a new clinical approach.
The
researchers found that delivery of a diphtheria toxin gene inhibited a
basic function of pancreatic tumor cells by over 95 percent, resulting
in significant cell death of pancreatic cancer cells six days after a
single treatment. They also demonstrated that the treatment targets
only pancreatic cancer cells and leaves normal cells alone, thus
providing a potential ‘therapeutic window.’ Further, they are
targeting a molecule that is found in over three-quarters of pancreatic
cancer patients.
“For
the pancreatic cancer world, this is very exciting,” says the study’s
lead author, molecular biologist Jonathan Brody, Ph.D., assistant
professor, Department of Surgery at Jefferson Medical College of Thomas
Jefferson University, who works closely with the Samuel D. Gross
Professor and Surgeon, Charles J. Yeo, M.D. “There are no effective
targeted treatments for pancreatic cancer, aside from surgery for which
only a minority of patients qualify. We are in great need of
translating the plethora of molecular information we know about this
disease to novel therapeutic ideas.
Pancreatic cancer is the fourth leading cause of cancer-related mortality in the U.S., reflecting the generally short survival
time of patients - often less than a year from diagnosis.
This
approach was originally developed in ovarian cancer cells by study
co-author Janet Sawicki, Ph.D., a member of the Kimmel Cancer Center,
and professor at the Lankenau Institute for Medical Research in
Wynnewood, Pennsylvania. She and her group had recent success in
reducing the size of ovarian tumors following treatment with diphtheria
toxin nanoparticles.
The
strategy is based on the fact that both ovarian and pancreatic cancer
cells significantly over-express a protein found on the cell membrane,
called mesothelin. The function of that molecule is unknown, but it is
found in the majority of pancreatic tumors and ovarian cancer tumors.
Other solid tumors also express mesothelin, but not at such a high
rate.
“We
don’t know completely why cancer cells repeatedly turn on mesothelin
genes to produce thesemembrane proteins, but it gives us a way to fool
the cell and hijack its machinery, to trick it into making other more
potent genes that will be detrimental to the cancer cells,” Brody says.
To
do that, the researchers devised an agent that consists of a bit of
mesothelin DNA connected to the gene that produces the toxin from
diphtheria, a highly contagious and potentially deadly bacteria, which
is now controlled through childhood DPT vaccination. “Naked” DNA is
then coated in a polymer to form nanoparticles that are taken up by the
cancer cells.
Inside
the cells, the agent performs its trickery. The nanoparticles
biodegrade and the cell machinery senses genetic material from
mesothelin. It activates the diphtheria toxin gene, which then turns on
production of the toxin which allows the toxin to then do its work on
the cancer cells, Brody says. Within 24 hours of delivery, the toxin
disrupted production of protein machinery by over 95 percent, and
within six days, a number of cancer cells die or are arrested.
“The
cancer thinks it is turning on mesothelin and once it gets started
reading that genetic code, it can’t stop,” he says. “So it will read
the bacteria’s DNA and produce the toxin which shuts down protein
production in the cancer cells.”
“It worked well in our cell culture models and now we are moving into pre-clinical experiments,” Brody says.
The
agent will not attack normal cells because the molecular machinery
needed to turn on mesothelin is not found in normal cells, Brody says.
Additionally, Sawicki has modified the diphtheria DNA to ensure that
toxin that might be released from dying cancer cells is not taken up by
healthy, normal cells.
But
the researchers are now perfecting even more stringent measures to
ensure safety, he says. “We can’t help being hopeful,” he says. “Our
findings suggest that such a strategy will work in the clinical setting
against the majority of pancreatic tumors.”
Media Only Contact:
Ed Federico
Thomas Jefferson University Hospital
Phone: (215) 955-6300
Published: 9/23/2008