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CPTAC, Seoul National University to Test Proteomic Workflows Including MRM-MS in Clinical Setting

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The National Cancer Institute last week announced a memorandum of understanding with Seoul National University Cancer Hospital under which SNUCH will test proteomic technologies, standards, workflows, and assays developed by NCI's Clinical Proteomic Tumor Analysis Consortium, CPTAC.

The effort aims to test the clinical applicability of the proteomic methods developed within CPTAC, and will focus on questions including generation and interpretation of clinical proteomics data as well as the ethical and legal issues involved in using such data in a clinical setting.

In terms of the project's technology emphasis, it will explore "several technologies and workflows … with one in particular being mass spectrometry," Henry Rodriguez, director of NCI's office of Cancer Clinical Proteomics Research and leader of the CPTAC initiative, told ProteoMonitor this week via email.

SNUCH researcher Youngsoo Kim, who is the acting coordinator for the MOU on the Korean side, told ProteoMonitor that the project will examine the clinical utility of "all the technologies that have been developed in the CPTAC program." He cited as particularly high priorities investigating multiple-reaction monitoring and immuno-MRM mass spec assays, developing a triple quadrupole-based platform for multiplexed protein assays, and verifying and validating candidate biomarkers in patient fluids.

CPTAC is a component of the NCI's larger Clinical Proteomic Technologies for Cancer initiative, which in 2011 launched its five-year, $75 million to $120 million second stage (PM 8/26/2011). CPTAC aims to identify proteins produced by alterations in cancer genomes and build methods and assays for their detection and measurement.

The program has established research centers at eight institutions including Washington University in St. Louis, the University of North Carolina, Boise State University, Pacific Northwest National Laboratory, the Broad Institute, Fred Hutchinson Cancer Research Center, Johns Hopkins University, and Vanderbilt University.

According to an update provided at the Human Proteome Organization's annual meeting in September by Chris Kinsinger, program manager in NCI's Office of Cancer Clinical Proteomics Research, groups from these centers have begun analyzing three tumor types – breast, colorectal, and ovarian – with the aim of profiling around 100 samples of each (PM 9/21/2012).

In the past, some researchers have criticized the current phase of CPTAC for continuing to focus significantly on biomarker discovery instead of working to move candidate biomarkers into the clinic.

For instance, last year, Leigh Anderson, CEO of clinical proteomics firm SISCAPA Assay Technologies and a participant in the first phase of CPTAC, told ProteoMonitor that many proteomics researchers hoped that the initiative's second phase "would attempt to implement a complete biomarker pipeline and determine for the first time how much clinical value there is to be found among the thousands of published biomarker candidates."

He added that the initiative's continued focus on biomarker discovery "to me looks like a retreat from the hard problem – verification – by kicking the can down the road while looking once more for an easier way around."

In light of these critiques, Anderson lauded the recently announced MOU, telling ProteoMonitor this week that, based on the details released by NCI, "it sounds like a positive thing … that they would go forward with this in a clinical environment."

"It's a useful supplement to what CPTAC is currently doing, which isn't so much focused on clinical diagnostic assays but rather on exploratory [work]," he said. "[Clinical proteomics] is now down to people taking candidate biomarkers, developing the assays, and actually going into clinical samples to evaluate them. And if that's what they are planning to do, that is really the important next step for biomarkers and mass spec technology."

Neither Rodriguez nor Kim offered specifics regarding biomarkers their collaboration might seek to focus on, but Rodriguez did note that MRM-MS "will be used for the verification of protein candidates, as this assay platform meets the needs of the high-throughput biology community."

CPTAC "has demonstrated the robust analytical performance for MRM-MS across laboratories and instrument platforms," he said.

Kim suggested, however, that work was still needed to determine the suitability of MRM-MS to the clinic. "First of all it has to be certified that MRM-MS is a fully developed, mature technology in terms of materials and platforms," he said. "We have not fully examined what is possible or not possible" with the technique.

Indeed, although triple quad-based MRM-MS is viewed by many as the most promising format for clinical proteomics assays, optimizing these assays for the clinic can be a complicated balancing act.

For instance, to increase assay speed – a key factor in validating and implementing protein biomarkers – researchers can reduce chromatography time. This, however, will hurt the assay's sensitivity – another important consideration. Likewise, sensitivity can be improved by using immuno-enrichment upfront of mass spec analysis to pull out the proteins of interest. However, this adds sample prep steps, which can reduce throughput and raise assay variability.

The CPTAC-SNUCH MOU is the latest in a number of efforts undertaken to tackle these issues.

In November, for example, a team including Anderson published on a MRM-MS-based peptide quantitation workflow with a sample cycle time as short as seven seconds (PM 11/16/2012). The technique, which achieved these cycle times by replacing traditional liquid chromatography with Agilent's RapidFire solid phase extraction system, enables a dramatic increase in the throughput of targeted protein assays.

In June, a multi-facility study led by Thermo Fisher Scientific's Biomarkers Research Initiatives in Mass Spectrometry Center examined the inter-lab reproducibility of MRM-MS assays applied to clinical samples treated with upfront protein enrichment techniques (PM 6/8/2012). The assays achieved inter-lab CVs ranging from 5 percent to 30 percent, with seven of the nine assays tested demonstrating cross-lab CVs of 21 percent or lower.

MRM-MS workflows continue to be challenged by "a lack of streamlined analytical workflow from sample preparation to data analysis in an automated fashion," Rodriguez said.

In addition to addressing such technical questions, the MOU will also provide the researchers with a chance to examine the more administrative and regulatory issues that will likely arise as proteomics moves into the clinic.

For instance, Rodriguez said, clinical proteomics will also face challenges due to "a lack of training of lab personnel familiar with these emerging technologies" and the fact that most research labs don't have the level of record keeping and documentation that would be required for a clinical or reference lab.

"An active clinical lab is regulated by the law and regulations of each country's health care system," Kim noted. "It's not like doing scientific research."

The MOU expands on a 2010 agreement with the Korea Institute of Science and Technology to "promote proteomic technology optimization and standards implementation," Rodriguez said, calling it a "natural extension" of that collaboration.

A start date for the project has not yet been set, Kim said.

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