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Novartis'
Alex Gaither on How New Tools are Redefining
Chemogenomics
By
Laurie
Sullivan
Senior
Technology Editor, Pharma DD
Alex Gaither is a
Speaker for the Chemogenomics conference part of CHI's
Discovery
on Target event in Boston, October 23-26, 2006.
October 11, 2006
Chemogenomics’
Evolvement:
From Cause-and-Effect Perturbation to Manipulation of
Genomic Response
Chemogenomics is classically defined as an individual’s
genomic response to a chemical compound. Alex Gaither, a
researcher at the Novartis Institutes of Biomedical
Research, believes that definition is evolving to
encompass the influence a drug has in the context of
different genetic backgrounds--heretofore coined as
pharmacogenomics.
Says
Gaither, “I’m beginning to see these historically
separate disciplines [chemogenomics and pharmacogenomics]
overlapping in many different ways even though
technically, from a bench perspective, they remain
slightly distinct when it comes to designing an experiment
or therapeutic approach.”
How
chemogenomics is changing, Gaither explains, is that in
the past, the genomic response to a chemical was defined
by microarrays: A compound was added to cells, and the
genome was subsequently surveyed for its effects on mRNA
modulation. With the advent of exciting new tools such as
cDNAs, shRNAs, and siRNAs, it has become possible to
actually go in and change that genomic response to the
chemical.
“That’s
how my own definition of chemogenomics has changed,”
notes Gaither. “It’s no longer a matter of simply
observing an individual’s genomic response [to a
compound]. It’s expanding to include our ability to alter
a person’s genomic response.”
Chemogenomics
and Small-Molecule Drug Discovery
Gaither
submits that RNAi technologies are currently the most
promising approach for discovery of small-molecule drug
targets, owing to the simple fact that an siRNA/shRNA can
phenocopy a compound. The addition of a chemical compound
triggers a pleiotropia of cellular effects, meaning that
it can bind multiple proteins. Each binding event results
in a distinct cellular response, collectively causing a
phenotype. By using an siRNA/shRNA that has been designed
against a specific gene, it is possible to mimic the
phenotype that would have otherwise been caused by the
chemical entity with greater specificity.
“siRNA
is so powerful because it allows us to dissect out the
exact genes that are influencing the activity of a
compound,” Gaither points out.
Gaither
adds that while things have not yet come completely to
fruition, ongoing developments in the research arena point
toward siRNAs as becoming a leading technology for
small-molecule drug development.
Gaither
clarifies that RNAi reagents are biological molecules and
as such, are not a chemogenomics approach on their own.
“How
chemogenomics will be influenced by RNAi is that the
latter can alter
a genomic response, allowing us to genetically tailor a
chemical therapy or use a chemical under defined genetic
conditions,” says Gaither. “RNAi approaches are able
to not only phenocopy a compound but also identify
additional pathways required for a compound’s activity,
a genetic sensitization paradigm. Since RNAi reagents are
biological molecules with a specific cellular
target/response (because it is known what gene it’s
hitting), the endpoint phenotype becomes easier to
understand.”
In
other words, if siRNAs are used to knock out gene X,
a certain phenotypic response is observed. But if a
chemical compound were used instead, the result could be
the same phenotypic response, but it would not be possible
to know all the genes bound by the compound. Therein lies
the power of the RNAi approach--increased specificity.
Chemogenomics’
Promise Comes With a Price…
The
key strength of using RNAi reagents in a chemogenomics
approach is the ability for genome-wide coverage.
“We’re
not doing this one gene at a time. We’re doing it with
all 20,000 genes simultaneously,” Gaither marvels.
“It’s an amazing advancement that within a ten-year
span, I’m now able to predict how a single gene can
affect the activity of a compound or phenotype under
study. The strength of using a chemogenomics approach
today is whole-genome functionalization, and I don’t
think there is any argument against that.”
Although
it is easy to tout how good this approach is, one of the
main weaknesses of the genome-wide chemogenomics approach
is that it is not easy technology to master. It requires a
very distinct expertise (or multiple types of expertise),
and extensive assay development--it can take months to
optimize a screen. Even after the screen has been
successfully completed, additional months are spent on
validating the results.
“The
power and the potential [of chemogenomics] are undeniably
there,” Gaither asserts. “The downfall is the expense.
Academic labs, for example, might have more difficulty
getting into routine genome-wide RNAi-based chemogenomics
experiments, simply because the necessary technology and
equipment can be prohibitively expensive.”
…Yet
It Is Broadly Applicable
A
chemogenomics approach to drug discovery could benefit
almost all therapeutic areas.
Like others, Gaither believes the indication where
chemogenomics will prove most useful is cancer.
“Simply
the idea of using RNAi to identify essential [genetic]
components affected by a chemical compound will allow for
patient stratification and biomarker identification, which
is where the pharmacogenomics component comes in. If a
person’s genome reveals they carry a specific mutation
or particular expression profile, it could call for
administration of one particular set of drugs vis-a-vis
another,” says Gaither. “That’s the clear benefit of
using RNAi technologies as a chemogenomics approach.”
Current
chemotherapies are known to work, but cause adverse side
effects. Chemoresistance is another significant problem,
meaning cells can become resistant to therapy and the
cancer progression is not fully inhibited, entering
remission. “To us, it simply means that the tumor cells
will find a way to mutate and tolerate the treatment only
and return five years later. Everyone is aware of these
issues, but there is really no clear way around them,”
Gaither says.
Identifying
novel approaches to combat disease is one application [of
chemogenomics], but a second, very important use would be
to improve current therapies.
“If
only we could screen standard-of-care, front-line
chemotherapies with RNAi libraries, we could likely find
novel combination therapies,” says Gaither. “We could
use chemogenomic approaches to better understand the
response to particular genetic perturbation. Thus we could
treat only those patients who could benefit from the
treatment, and possibly identify combination therapies
that could improve the therapeutic window of efficacy.
Then chemotherapies could be designed to be less toxic and
more specific to an individual’s cancer. Taking this
approach, I think we could vastly improve the way in which
patients are treated.”
Case
in point.
Gaither singles out Agenerase (amprenivir), from Vertex
and GlaxoSmithKline, as a good example. Agenerase is an
FDA-approved protease inhibitor for treatment of HIV, but
it’s being studied for additional indications. Using a
chemogenomics approach, Agenerase has been shown to be
efficacious in cancer, and it has also shown promise in
other, non-HIV viral infections (e.g., HCV).
“Neurodegeneration
is another therapeutic indication where we know RNAi
chemogenomics screens would be beneficial. To screen
disease-associated mutations against certain chemicals or
RNAi reagents, find the best combination of targets (e.g.
with the best efficacy against those diseases), and treat
an individual’s genetic profile appropriately, depending
upon the mutations (or lack of mutations) they carry,”
adds Gaither. “Although this is an optimistic endeavor,
it could be a direct application of chemogenomics
tools.”
Chemogenomics’
Best-Practice Approach to Drug Discovery
“Cell-based
assays that directly translate in
vivo are the best model systems,” says Gaither.
“Everything should be done in cell lines derived from an
animal or in cells amenable to transplantation (xenograft)
into a live animal.”
A
major problem with the cell-based model is the lack of
correlation between the cellular phenotype and the
activity in vivo.
“Since adopting a chemogenomics paradigm in our
research, we are trying to use only those cell lines that
are directly relevant to the specific disease being
analyzed,” notes Gaither.
Cancer
again serves as an obvious example. Traditionally, people
have carried out chemogenomics experiments in cell-based
assays, looking for the cause-and-effect relationships and
phenotypes, opting to worry about how the effects will
translate in vivo
at a later time. For drug discovery efforts, it is more
efficient to study cells that are derived directly from
tumors or tumor cells, which can be transplanted back into
animals, where it is possible to immediately look for in
vivo efficacy.
“Being
able to condense our screening process by running
model-system assays that can be tested directly in a live
animal is a major advance. There’s just an enormous
disconnect between a cell-based assay and an animal,”
Gaither concludes. “The idea is that if we can get one
step closer to in
vivo efficacy during our screening process and drug
target development, we can be one step closer to success
in humans.”
Copyright
2006, All Rights Reserved. Cambridge Healthtech Institute.
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