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Signals in the noise (Part 1 of 2)
November 2012
EDIT CONNECT
SHARING OPTIONS:
STORY PART 1 of 2
A lone technician sits before a computer monitor, watching a
visual
cacophony of images and data stream past her face, her retinas slowly
becoming inured to the assault on her senses—so much so, in fact, that it takes
a
moment for her to realize that the screen has suddenly stopped shifting and a
single form splays across the screen. Picking up the phone, she punches in
a
number and waits for the other person to answer. They have the recommendation
they've been waiting for.
Jodie Foster in a scene from Carl Sagan's Contact? Possibly.
But it might also be any
number of researchers and
clinicians working in research hospitals and biopharmaceutical companies across
the country, as informatics advances push the
capabilities of personalized
medicine to the point where clinicians can get vital diagnostic and theranostic
information in real time to assist them in
making real-life decisions about
their patients, and effortlessly feed that information back to clinical
researchers who are trying to develop the next
generation of therapeutics.
Biomarker bonanza
As mentioned in the first half of our two-part series on
trends in personalized medicine ("A
companion in your corner," ddn October 2012), regulators and pharma
companies are increasingly pushing to develop diagnostic tests that
designate
what patients are best suited to receive what drugs, whether due to improved
efficacy or safety. The canonical example is, of course, the
HER2 biomarker and
its use in determining whether a breast cancer patient should receive a drug
like Herceptin that specifically targets Her2-positive
tumors.
Biomarker signatures that only involve one or two genes,
however, really only give us so much
of an edge. If that biomarker is found in
40 percent of patients tested, that is still a lot of patients, and this merely
tells you it has a better
chance of working in Jessica, who also carries that
biomarker.
Without minimizing the work that
went into identifying and
validating those single biomarkers, these tests are only really part of the
equation—the low-hanging fruit, if you will. It
's the equivalent of
fingerprinting a suspect on the basis of one line of a whorl in one quadrant of
the thumb. Fingerprints are much more complex,
which is why they can be used to
identify individuals.
"A single biomarker will only give you so
much insight, and
as we progress to more complex diseases, combination signatures become
increasingly important," echoes Ger Brophy, general manager
of new product
development at GE Healthcare
in Fairfield, Conn.
As an example, at the Markers in Cancer Meeting
in October,
Roland Kappler and colleagues from the Dr. Von Hauner Children's Hospital in
Munich described their efforts to identify more complex
genetic signatures as
prognostic markers in hepatoblastoma in children. Examining the methylation
patterns of the RASSF1 gene and correlating those
patterns with clinical data,
the researchers were able to identify a distinct epigenetic pattern that
tightly linked with the likelihood of metastasis
and overall survival rates in
patients.
Looking beyond
genomics
But genomics is only one part of the biomarker equation,
albeit
possibly the most linear when it comes to linking biomarker with
outcome. As we begin to expand our appreciation of an individual's biomedical
fingerprint, it will likely be necessary to expand into other methodologies.
This move has started on some fronts.
In April, Research Triangle Park, N.C.-based Metabolon
announced a research initiative with Osaka, Japan's Takeda Pharmaceutical to
identify novel therapeutics and biomarkers using its metabolomics expertise.
And in August, the company announced its
completion of the acquisition of
lipid-metabolism specialist Lipomics Technologies, further expanding its
technology base.
"We are the leader in the
commercialization of metabolomics,
with a profitable commercial life-sciences service business, and have launched
the world's first metabolomics-based
diagnostic test for type 2 diabetes risk
based on biomarkers that measure insulin resistance," said Metabolon CEO Dr.
John Ryals in announcing the
acquisition. "We expect that in 2013, we will be
marketing additional diagnostic products aimed at diseases related to obesity
and cancer, and are
committed to maintaining our position as the world's leader
in metabolomics."
Companies like Ezose Sciences, based in Pine Brook, N.J.,
meanwhile, are attempting to
leverage expertise in glycomics and the company's
GlycanMap platform as the basis of a diagnostics pipeline. In April, the
company announced a
collaboration with Hirosaki University to identify
potential glycomic biomarkers to predict and monitor prostate and other
urological cancers.
And even cellomics has started to make inroads into the
biomarker world. Also presenting at the Markers in Cancer Meeting, researchers
from
Durham, N.C.-based Argos Therapeutics discussed efforts to
identify
cell-surface signatures for patient response to its immunotherapy candidate
AGS-003 in patients with metastatic renal cell carcinoma.
Argos researchers applied informatics methodology more
commonly used in microarray analysis to flow cytometry
of cytotoxic T cells and
identified combinatorial expression patterns of cell surface markers that
correlated with superior outcomes in patients
receiving AGS-003 and sunitinib.
By parsing the data even further, they were able to identify other biomarker
signatures, which they described as
markers of immune function, or MIFs, and
tightly correlated with progression-free survival and overall survival outcomes
in the study patients.
Driven by data
The inherent complexity of these signatures, however,
increases the need for informatics solutions to help distinguish the
signal
from the noise in identifying true signatures. Unlike the HER2 tests, we are no
longer looking at a simple binary yes-no answer.
Researchers aren't just limiting themselves to 'omics data,
either.
"While the in-vitro
signature—e.g., genetic biomarkers—is
important, the in-vivo stage—e.g., imaging—is also very important to
getting a
complete answer," says Brophy. "The question then becomes how do you
combine data from a variety of sources such as electronic medical records
(EMRs), pathology, radiology, etc."
For GE Healthcare—which has extensive expertise in medical
imaging
methodologies such as PET, MRI and CT scans—part of the answer came in
moving that expertise into the world of pathology.
"The digitization of radiology revolutionized that field,
and we feel the time is now right to digitize pathology and take it
from a
subjective art to an objective science," Brophy adds. "This would give pharma a
quantitative tool to monitor the performance of a drug on
pathology slides,
rather than rely solely on the qualitative analysis of a pathologist."
To that
end, GE Healthcare recently launched Omnyx, a joint
venture with the University of Pittsburgh Medical Center (UPMC). According to
Brophy, UPMC brings an extensive collection
of annotated tissue slides and
offers Omnyx access to a constant influx of thousands of patients each year.
The focus is on cancer diagnostics and
developing systems where clinicians and
pathologists can store, retrieve, annotate and share data easily and quickly
with colleagues.
"While the scanner is the most obvious component, the
software interface and back end is key to the system," he
adds. "And of course,
the challenge is in not just developing a tool that reflects what the
pathologist is doing now, but also how they will be
working in the future."
"Clinical diagnostics are not new—people have been
performing urine
tests or blood work for years," adds Trish Meek, director of
life-sciences product strategy at Waltham, Mass.-based Thermo Fisher Scientific
Inc. "The challenges of molecular
diagnostics, however, are quite unique as
researchers try to perform standard assays, while always incorporating new
technologies and techniques into
their practice."
As its clients' needs evolved, Thermo Fisher Scientific
extended its knowledge
with lab information systems (LIS) and lab information
management systems (LIMS) into helping pharma customers with biomarker
identification and
validation—and ultimately into research hospitals.
"We work with the customer to take them beyond
the
traditional LIS, so our job is still about operations on one side, but it is
also about making sure the information is clear and actionable on the
other,"
says Meek. "That's why we developed the web-based interface for the end user."
As
biomarker signatures become more complex, pharma
companies are likely to rely more heavily on their diagnostic partners and can
expect a significant
shift in the clinical trials landscape.
"Biomarker validation will become an increasingly
important
part of the clinical trial process," Brophy offers. "As pharma companies
approach the Phase IIb trial of their new drug without a marker,
they may begin
to get worried that they don't have a companion diagnostic."
GE Healthcare's
2010 acquisition of molecular diagnostics
specialist Clarient, which is based in Aliso Viejo, Calif., was a step toward
addressing this need.
"GE and Clarient are in a number of discussions with pharma
companies as to how we can help, leveraging
our CLIA-certified labs to identify,
develop and validate these diagnostic resources," adds Brophy.
Code: E111228 Back |
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