PROTEIN TRANSDUCTION: - Moores Cancer Center

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at UCSD. The larger molecules
contain much more information
— instructions that could be the
basis for new drugs that would be
more specific in their function,
meaning they would work at smaller
doses and have fewer side effects.
“I like to use the analogy of a
house with a mail slot,” says Dowdy.
“The small molecule is the equivalent
of a single-page letter. It can
go in easily, but contains limited
information. In contrast, with
protein transduction we can put
a computer through the same mail
slot, have it reassembled on the
other side, and get vastly more
information inside the house,
or cell, than ever before.”
Based on his work to date,
and the work now of many others,
it appears that virtually every
chemical structure can utilize this
approach — nucleic acids, proteins,
peptides, synthetic molecules,
carbohydrates and more.
“So now, in theory, scientists
could redesign the existing smallmolecule
drug libraries to these
larger size molecules and add much
more specific information,” he said.
“This could represent an entirely
new approach to treating disease;
not only cancer, but others ranging
from heart disease to headaches
and the common cold.”
Dowdy acknowledges that the
field has not yet matured enough
to know exactly how well this will
work in practice. Nevertheless, the
field is moving forward rapidly and
the preclinical work in animals
looks very promising.
His own laboratory is focusing
on using protein transduction for
cancer. He and his colleagues have
Protein transduction is like putting a
computer through a mail slot. We can
get vastly more information inside the
cell than ever before.
— Steven Dowdy, Ph.D.
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been working to introduce tumor
suppressor proteins, such as the
p53 protein, into mice whose cells
have lost this function. They are
working with two mouse models
of cancer. One type develops
peritoneal malignancies, such as
ovarian or pancreatic cancer, and
the other develops lymphoma.
“About 50 percent of the mice
we’ve treated, all with aggressive
and terminal disease, have
achieved long-term survival,”
Dowdy said of the work that has
not yet been published. “However,
doing this in a mouse is a long
way from doing it in a human.
Still, we’ve shown that we can
reconstitute tumor suppressor
function and stop the cancerous
process in models that closely
mimic human disease.”
If his results continue to hold
up over time, the next step would
be to move this work into clinical
trials, which Dowdy says is still
several years away.
Dowdy’s laboratory is also
looking to develop new molecules
that could be tailored to the job at
hand. By attaching multiple cargo
domains to the PTD, like cars to
a train, he hopes to build highly
selective, composite molecules.
An example of the potential
utility of this approach is found
in doxyrubicin, a widely used anticancer
drug.
“Doxyrubicin is a great drug, but
it is susceptible to a protein called
p-glycoprotein, which acts like a
pump in the cancer cell to push the
drug out. This problem is often
worse in late-stage and recurrent
disease,” said Dowdy. “With our
transducible approach, we could,
theoretically, add modules that
would enable us to selectively
bypass the p-glycoprotein and
deliver the drug directly to the
nucleus in tumor cells and not the
normal cells.”
Dowdy also said it would be possible
to add an imaging compound
to a drug warhead and “simultaneously
image the death of the
tumor, which would give us an idea
of how well the drug is working.”
By adding these layers of selectivity,
the theory goes, one can get
further and further discriminations
to hit the bull’s eye of the tumor
while sparing the surrounding normal
cells.
“This is the ultimate goal,” he
said. “It may be optimistic at this
point, but I believe some form of
this modular approach will be able
to move forward and will give us
the kind of selectivity and versatility
that small molecules simply are not
capable of providing.”
—Nancy Stringer, Director,
Cancer Center Communications
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