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NCI CPTC Annual Meeting Features Call for Near-Term Clinical Applications, Focus on PTMs

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By Adam Bonislawski

The fourth annual meeting of the National Cancer Institute's Clinical Proteomics Technologies for Cancer initiative opened this week in Bethesda, Md., with a plea from Paula Kim, chair of the advocacy organization Translating Research Across Communities, for proteomics researchers to focus on the question of what their work would "do to help patients in the near term."

"What's going to happen now, a year from now, two years from now, three years from now?" she asked in her opening talk, noting "that's the timeframe that resonates with policymakers; that's the timeframe that resonates with patients."

Such calls for clinical applications have become common features of the proteomics landscape. At last year's meeting CPTC director Henry Rodriguez said the field's "promise has not really turned out what we thought it would be," while Leigh Anderson, founder and president of the Plasma Proteome Institute, asserted that thus far clinical proteomics "has had no impact at all" (PM 09/10/2009).

The five-year, $104 million CPTC initiative was launched in 2006 with the aim of building a foundation of technologies and standards to help move proteomics into the clinic – with an emphasis on applications useful in cancer research. This June, NCI announced that it would be providing $75 million to $120 million to fund a second five-year phase of the CPTC, which will seek to build on the first phase by establishing a collaborative team of six to eight Proteome Characterization Centers working to systematically define the functional cancer proteome and discover and verify protein cancer biomarkers (PM 07/09/2010).

This week's presentations – while largely avoiding promises of the sort of near-term clinical uses Kim called for – provided a wide-ranging overview of the discovery and technology development work currently underway in the field.

Among the subjects covered at the conference, post-translational modifications emerged as a main consideration, with a session of presentations devoted to the subject and a number of other talks discussing it, as well.

"One of the questions we had was to plow through different kinds of [post-translational modifications] and try to understand whether they were associated with cancer," Purdue professor Fred Regnier said during his presentation of his team's investigation into the relationship between breast cancer and oxidative stress. By examining the carbonylation patterns of plasma proteins isolated from six breast cancer patients, the researchers have identified oxidation signatures potentially indicative of breast cancer.

Brad Gibson, director of the chemistry core at the Buck Institute for Age Research and one of Regnier's collaborators on the PTM work, presented research done over the last year through the Clinical Proteomic Technology Assessment for Cancer program.

Gibson discussed his group's work on lectin enrichment for glycoproteins, TiO2 and IMAC enrichment for phosphoproteins, and biotin-hydrazide and avidin enrichment for carbonyl groups to study protein oxidation.

His group is also working to develop standards for a variety of PTMs that can be used in the development of MRM assays, he said – a challenge facing PTM research that Regnier also raised during his presentation.

David Tabb, assistant professor at Vanderbilt University's Ingram Cancer Center, detailed advances in his team's TagRecon software, specifically advances in its use for identification of PTMs by blind searching, where the mass and specificity of peptide modifications are unknown. The researchers have added secondary scoring of matches to improve identifications, improved their estimation of false discovery rates, and developed patterns of mass shifts from various datasets to better substantiate PTM identifications.

Several scientists presenting work not focused specifically on PTMs nonetheless touched on the subject as well.

William Old, assistant research professor at the University of Colorado, raised the need for improved MS/MS spectral libraries, noting that, among other drawbacks they "poorly represent post-translational modifications."

To address this issue the researchers have developed a kinetic model of gas-phase peptide fragmentation that he said enables prediction of MS/MS spectra from any peptide sequence. The model, he said, has shown improved peptide identification compared to current methods and will allow the de novo design of SRM mass spec assays.

In particular, Old said, his team is "focusing right now on phosphorylation," which he noted "is one of the more difficult modifications to model due to the neutral loss and the complex chemistry that results from adjacent amino acids."

Using phosphoprotein data developed by the Institute of Systems Biology, the Colorado researchers are incorporating phosphorylation into their kinetic model and plan to begin within the next month fitting this phophorylation model against spectral libraries, Old said.

Phosphorylation was similarly a subject of MIT researcher Forest White's presentation, which detailed his lab's work on protein signaling pathways in cancer, primarily breast cancer and glioblastoma.

By examining phosphorylation levels of proteins in a variety of signaling pathways driving cellular migration and proliferation, White hopes to identify potential drug targets and develop protein signatures enabling early diagnosis and the guidance of therapy.

"One of the big challenges the community faces right now is getting from genetic mutation to therapeutic targets. How do mutations affect the cell and which drugs would be the best options for patients who have these mutations? The way that we look at that is by looking at signaling," he said.

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