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Signals in the noise (Part 1 of 2)
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.
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.