BIO ENGINEERED DECOY PROTEIN MAY STOP CANCER FROM SPREADING
A team of Stanford
researchers has developed a protein therapy that disrupts the process that
causes cancer cells to break away from original tumor sites, travel through the
blood stream and start aggressive new growths elsewhere in the body.
This process, known as
metastasis, can cause cancer to spread with deadly effect.
"The majority of
patients who succumb to cancer fall prey to metastatic forms of the
disease," said Jennifer Cochran, an associate professor of bioengineering
who describes a new therapeutic approach in Nature Chemical Biology.
Today doctors try to
slow or stop metastasis with chemotherapy, but these treatments are
unfortunately not very effective and have severe side effects.
The Stanford team
seeks to stop metastasis, without side effects, by preventing two proteins --
Axl and Gas6 -- from interacting to initiate the spread of cancer.
Axl proteins stand
like bristles on the surface of cancer cells, poised to receive biochemical
signals from Gas6 proteins.
When two Gas6 proteins
link with two Axls, the signals that are generated enable cancer cells to leave
the original tumor site, migrate to other parts of the body and form new cancer
nodules.
To stop this process
Cochran used protein engineering to create a harmless version of Axl that acts
like a decoy. This decoy Axl latches on to Gas6 proteins in the blood stream
and prevents them from linking with and activating the Axls present on cancer
cells.
In collaboration with
Professor Amato Giaccia, who heads the Radiation Biology Program in Stanford's
Cancer Center, the researchers gave intravenous treatments of this
bioengineered decoy protein to mice with aggressive breast and ovarian cancers.
Mice in the breast
cancer treatment group had 78 percent fewer metastatic nodules than untreated
mice. Mice with ovarian cancer had a 90 percent reduction in metastatic nodules
when treated with the engineered decoy protein.
"This is a very
promising therapy that appears to be effective and non-toxic in pre-clinical
experiments," Giaccia said. "It could open up a new approach to
cancer treatment."
Giaccia and Cochran
are scientific advisors to Ruga Corp., a biotech startup in Palo Alto that has
licensed this technology from Stanford. Further preclinical and animal tests
must be done before determining whether this therapy is safe and effective in
humans.
Greg Lemke, of the
Molecular Neurobiology Laboratory at the Salk Institute, called this "a
prime example of what bioengineering can do" to open up new therapeutic
approaches to treat metastatic cancer.
"One of the
remarkable things about this work is the binding affinity of the decoy
protein," said Lemke, a noted authority on Axl and Gas6 who was not part
of the Stanford experiments.
"The decoy
attaches to Gas6 up to a hundredfold more effectively than the natural
Axl," Lemke said. "It really sops up Gas6 and takes it out of
action."
Directed Evolution
The Stanford approach
is grounded on the fact that all biological processes are driven by the
interaction of proteins, the molecules that fit together in lock-and-key
fashion to perform all the tasks required for living things to function.
In nature proteins
evolve over millions of years. But bioengineers have developed ways to
accelerate the process of improving these tiny parts using technology called
directed evolution. This particular application was the subject of the doctoral
thesis of Mihalis Kariolis, a bioengineering graduate student in Cochran's lab.
Using genetic
manipulation, the Stanford team created millions of slightly different DNA
sequences. Each DNA sequence coded for a different variant of Axl.
The researchers then
used high-throughput screening to evaluate over 10 million Axl variants. Their
goal was to find the variant that bound most tightly to Gas6.
Kariolis made other
tweaks to enable the bioengineered decoy to remain in the bloodstream longer
and also to tighten its grip on Gas6, rendering the decoy interaction virtually
irreversible.
Yu Rebecca Miao, a
postdoctoral scholar in Giaccia's lab, designed the testing in animals and
worked with Kariolis to administer the decoy Axl to the lab mice. They also did
comparison tests to show that sopping up Gas6 resulted in far fewer secondary
cancer nodules.
Irimpan Mathews, a
protein crystallography expert at the SLAC National Accelerator Laboratory,
joined the research effort to help the team better understand the binding
mechanism between the Axl decoy and Gas6.
Protein
crystallography captures the interaction of two proteins in a solid form,
allowing researchers to take X-ray-like images of how the atoms in each protein
bind together. These images showed molecular changes that allowed the bioengineered
Axl decoy to bind Gas6 far more tightly than the natural Axl protein.
Next steps
Years of work lie
ahead to determine whether this protein therapy can be approved to treat cancer
in humans. Bioprocess engineers must first scale up production of the Axl decoy
to generate pure material for clinical tests. Clinical researchers must then
perform additional animal tests in order to win approval for and to conduct
human trials. These are expensive and time-consuming steps.
But these early,
hopeful results suggest that the Stanford approach could become a non-toxic way
to fight metastatic cancer.
Glenn Dranoff, a
professor of medicine at Harvard Medical School and a leading researcher at the
Dana-Farber Cancer Institute, reviewed an advance copy of the Stanford paper
but was otherwise unconnected with the research. "It is a beautiful piece
of biochemistry and has some nuances that make it particularly exciting,"
Dranoff said, noting that tumors often have more than one way to ensure their
survival and propagation.
Axl has two protein
cousins, Mer and Tyro3, that can also promote metastasis. Mer and Tyro3 are
also activated by Gas6.
"So one
therapeutic decoy might potentially affect all three related proteins that are
critical in cancer development and progression," Dranoff said.
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