PASADENA, Calif. - A California Institute of Technology
(Caltech)-led team of researchers and clinicians has published the
first proof that a targeted nanoparticle - used as an experimental
therapeutic and injected directly into a patient's bloodstream -
can traffic into tumors, deliver double-stranded small interfering
RNAs (siRNAs), and turn off an important cancer gene using a
mechanism known as RNA interference (RNAi). Moreover, the team
provided the first demonstration that this new type of therapy,
infused into the bloodstream, can make its way to human tumors in a
dose-dependent fashion - i.e., a higher number of nanoparticles
sent into the body leads to a higher number of nanoparticles in the
tumor cells.
These results, published in the March 21 advance online edition
of the journal Nature, demonstrate the feasibility of using
both nanoparticles and RNAi-based therapeutics in patients, and
open the door for future "game-changing" therapeutics that attack
cancer and other diseases at the genetic level, says Mark Davis,
the Warren and Katharine Schlinger Professor of Chemical
Engineering at Caltech, and the research team's leader.
The discovery of RNA interference, the mechanism by which double
strands of RNA silence genes, won researchers Andrew Fire and Craig
Mello the 2006 Nobel Prize in Physiology or Medicine. The
scientists first reported finding this novel mechanism in worms in
a 1998 Nature paper. Since then, the potential for this type
of gene inhibition to lead to new therapies for diseases like
cancer has been highly touted.
"RNAi is a new way to stop the production of proteins," says
Davis. What makes it such a potentially powerful tool, he adds, is
the fact that its target is not a protein. The vulnerable areas of
a protein may be hidden within its three-dimensional folds, making
it difficult for many therapeutics to reach them. In contrast, RNA
interference targets the messenger RNA (mRNA) that encodes the
information needed to make a protein in the first place.
"In principle," says Davis, "that means every protein now is
druggable because its inhibition is accomplished by destroying the
mRNA. And we can go after mRNAs in a very designed way given all
the genomic data that are and will become available."
Still, there have been numerous potential roadblocks to the
application of RNAi technology as therapy in humans. One of the
most problematic has been finding a way to ferry the therapeutics,
which are made up of fragile siRNAs, into tumor cells after direct
injection into the bloodstream. Davis, however, had a solution.
Even before the discovery of RNAi, he and his team had begun
working on ways to deliver nucleic acids into cells via systemic
administration. They eventually created a four-component system -
featuring a unique polymer - that can self-assemble into a
targeted, siRNA-containing nanoparticle. The siRNA delivery system
is under clinical development by Calando Pharmaceuticals, Inc., a
Pasadena-based nanobiotech company.
"These nanoparticles are able to take the siRNAs to the targeted
site within the body," says Davis. Once they reach their target -
in this case, the cancer cells within tumors - the nanoparticles
enter the cells and release the siRNAs.
The scientific results described in the Nature paper are
from a Phase I clinical trial of these nanoparticles that began
treating patients in May 2008. Phase I trials are, by definition,
safety trials; the idea is to see if and at what level the drug or
other therapy turns harmful or toxic. These trials can also provide
an in-human scientific proof of concept - which is exactly what is
being reported in the Nature paper.
Using a new technique developed at Caltech, the team was able to
detect and image nanoparticles inside cells biopsied from the
tumors of several of the trial's participants. In addition, Davis
and his colleagues were able to show that the higher the
nanoparticle dose administered to the patient, the higher the
number of particles found inside the tumor cells - the first
example of this kind of dose-dependent response using targeted
nanoparticles.
Even better, Davis says, the evidence showed the siRNAs had done
their job. In the tumor cells analyzed by the researchers, the mRNA
encoding the cell-growth protein ribonucleotide reductase had been
degraded. This degradation, in turn, led to a loss of the
protein.
More to the point, the mRNA fragments found were exactly the
length and sequence they should be if they'd been cleaved in the
spot targeted by the siRNA, notes Davis. "It's the first time
anyone has found an RNA fragment from a patient's cells showing the
mRNA was cut at exactly the right base via the RNAi mechanism," he
says. "It proves that the RNAi mechanism can happen using siRNA in
a human."
"There are many cancer targets that can be efficiently blocked
in the laboratory using siRNA, but blocking them in the clinic has
been elusive," says Antoni Ribas, associate professor of medicine
and surgery at UCLA's Jonsson Comprehensive Cancer Center. "This is
because many of these targets are not amenable to be blocked by
traditionally designed anti-cancer drugs. This research provides
the first evidence that what works in the lab could help patients
in the future by the specific delivery of siRNA using targeted
nanoparticles. We can start thinking about targeting the
untargetable."
"Although these data are very early and more research is needed,
this is a promising study of a novel cancer agent, and we are proud
of our contribution to the initial clinical development of siRNA
for the treatment of cancer," says Anthony Tolcher, director of
clinical research at South Texas Accelerated Research Therapeutics
(START).
"Promising data from the clinical trials validates our years of
research at City of Hope into ribonucleotide reductase as a target
for novel gene-based therapies for cancer," adds coauthor Yun Yen,
associate director for translational research at City of Hope. "We
are seeing for the first time the utility of siRNA as a cancer
therapy and how nanotechnology can target cancer cells
specifically."
The Phase I trial - sponsored by Calando Pharmaceuticals - is
proceeding at START and UCLA's Jonsson Comprehensive Cancer Center,
and the clinical results of the trial will be presented at a later
time. "At the very least, we've proven that the RNAi mechanism can
be used in humans for therapy and that the targeted delivery of
siRNA allows for systemic administration," Davis says. "It is a
very exciting time."
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