Short strands of RNA can be used to selectively turn off cancer genes. |
By sequencing cancer-cell genomes,
scientists have discovered vast numbers of genes that are mutated, deleted, or
copied in cancer cells. This treasure trove is a boon for researchers seeking
new drug targets, but it is nearly impossible to test them all in a timely
fashion.
To help speed up the process, Massachusetts
Institute of Technology (MIT) researchers have developed RNA-delivering
nanoparticles that allow for rapid screening of new drug targets in mice. In
their first mouse study, done with researchers at Dana-Farber Cancer Institute
and the Broad Institute, they showed that nanoparticles that target a protein
known as ID4 can shrink ovarian tumors.
The nanoparticle system, described in an
online edition of Science Translational Medicine, could relieve a
significant bottleneck in cancer-drug development, says Sangeeta Bhatia, the
John and Dorothy Wilson Professor of Health Sciences and Technology and
Electrical Engineering and Computer Science and a member of the David H. Koch
Institute for Integrative Cancer Research at MIT.
“What we did was try to set forth a
pipeline where you start with all of the targets that are pouring out of
genomics, and you sequentially filter them through a mouse model to figure out
which ones are important. By doing that, you can prioritize the ones you want
to target clinically using RNA interference, or develop drugs against,” says
Bhatia, one of the paper’s senior authors.
William Hahn, an associate professor of
medicine at Harvard Medical School and the paper’s other senior author, is the
leader of Project Achilles, a collaborative effort to identify promising new
targets for cancer drugs from the flood of data coming from the National Cancer
Institute’s cancer-genome-sequencing project.
Among those potential targets are many
considered to be “undruggable,” meaning that the proteins don’t have any
pockets where a traditional drug could bind to them. The new nanoparticles,
which deliver short strands of RNA that can shut off a particular gene, may
help scientists go after those undruggable proteins.
“If we could figure out how to make this
work [in humans], it would open up a whole new class of targets that hadn’t
been available,” says Hahn, who is also director of the Center for Cancer
Genome Discovery at Dana-Farber and a senior associate member of the Broad
Institute.
Lead authors of the paper are Yin Ren, an
MD/PhD student in Bhatia’s laboratory, and Hiu Wing Cheung, a postdoctoral
researcher in Hahn’s laboratory.
An abundance of targets
Through Project Achilles, Hahn and his colleagues have been testing the
functions of many of the genes disrupted in ovarian cancer cells. By revealing
genes critical to cancer-cell survival, this approach has narrowed the list of
potential targets to several dozen.
Typically, the next step in identifying a
good drug target would be to genetically engineer a strain of mice that are
missing (or overexpressing) the gene in question, to see how they respond when
tumors develop. However, this normally takes two to four years. A much faster
way to study these genes would be simply to turn them off after a tumor
appears.
RNA interference (RNAi) offers a promising
way to do that. During this naturally occurring phenomenon, short strands of
RNA bind to the messenger RNA (mRNA) that delivers protein-building
instructions from the cell’s nucleus to the rest of the cell. Once bound, the
mRNA molecules are destroyed and their corresponding proteins never get made.
Scientists have been pursuing RNAi as a
cancer treatment since its discovery in the late 1990s, but have had trouble
finding a way to safely and effectively target tumors with this therapy. Of
particular difficulty was finding a way to get RNA to penetrate tumors.
Bhatia’s laboratory, which has been working
on RNAi delivery for several years, joined forces with Hahn’s group to identify
and test new drug targets. Their goal was to create a mix-and-dose technique
that would allow researchers to mix up RNA-delivery particles that target a
particular gene, inject them into mice, and see what happens.
Shrinking tumors
In their first effort, the researchers decided to focus on the ID4 protein
because it is overexpressed in about a third of high-grade ovarian tumors (the
most aggressive kind), but not in other cancer types. The gene, which codes for
a transcription factor, appears to be involved in embryonic development: It
gets shut down early in life, then somehow reactivates in ovarian tumors.
To target ID4, Bhatia and her students
designed a new type of RNA-delivering nanoparticle. Their particles can both
target and penetrate tumors, something that had never before been achieved with
RNA interference.
On their surface, the particles are tagged
with a short protein fragment that allows them to enter tumor cells. Those
fragments are also drawn to a protein found on tumor cells, known as p32. This
fragment and many similar ones were discovered by Erkki Ruoslahti, a professor
at the Sanford-Burnham Medical Research Institute at the University of
California at Santa Barbara, who is also an author of the new paper.
Within the nanoparticles, strands of RNA
are mixed with a protein that further helps them along their journey: When the
particles enter a cell, they are encapsulated in membranes known as endosomes.
The protein-RNA mixture can cross the endosomal membrane, allowing the
particles to get into the cell’s main compartment and start breaking down mRNA.
In a study of mice with ovarian tumors, the
researchers found that treatment with the RNAi nanoparticles eliminated most of
the tumors.
The researchers are now using the particles
to test other potential targets for ovarian cancer as well as other types of
cancer, including pancreatic cancer. They are also looking into the possibility
of developing the ID4-targeting particles as a treatment for ovarian cancer.
