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NCI Kicks Off Second Stage of Clinical Proteomic Technologies for Cancer Initiative

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This story originally ran on Aug. 22 and has been updated to include comments from a participant.

By Adam Bonislawski

The National Cancer Institute announced this week the eight proteome characterization centers that will be taking part in the second issuance of its Clinical Proteomic Technologies for Cancer initiative.

The participating centers include facilities at 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.

The CPTC initiative's second stage – which is currently slated as a five-year, $75 million- to $120 million-project – comprises two parts: a discovery stage wherein the characterization centers selected for the program will look for potential biomarkers in tumor tissue samples, and a verification stage wherein the researchers will investigate smaller biomarker sets composed of the most promising candidates identified in discovery (PM 07/09/2010).

The work builds on the initial five-year, $104 million CPTC initiative launched in 2006 and aimed at building a foundation of technologies and standards to advance the application of proteomics to cancer research. That project established five multidisciplinary, multi-institution research centers and developed collaborations with more than 60 public and private institutions around the world.

For the second stage, the principal investigators for the characterization centers are Matthew Ellis and Reid Townsend at Washington University in St. Louis; Xian Chen at UNC; Morgan Giddings at Boise State; Richard Smith at PNNL; Steven Carr at the Broad Institute; Amanda Paulovich at Fred Hutchinson; Daniel Chan, Zhen Zhang, and Hui Zhang at Johns Hopkins; and Daniel Leibler at Vanderbilt University.

Precisely what types of cancer the researchers will be investigating is still being determined, Giddings told ProteoMonitor. When the second issuance was announced last year, CPTC officials indicated the work would likely be done in ovarian, kidney, breast, and glioblastoma tumors. However, Giddings said, based on discussions among the initiative's participants at the second phase kick-off meeting held this week in Bethesda, Md., it's likely the researchers will narrow their focus to just "a few of those from NIH's original list."

"If the group can show that we can take one or two cancers and really make headway and good progress, then that will be a demonstration to say, ok, this is worth going and doing in other cancers," she said.

One of the primary goals of the second issuance is to integrate genomic and proteomic data in the search for cancer biomarkers, the idea being, Giddings said, that "we can find a lot of interesting things when we go off the [protein database] map and just look at the genome, and we can then see how does all our proteomic data map to the genome."

This priority, Giddings noted, has also factored into the decision to narrow the project's focus.

"If we're really going to link genome and proteome together, we need a cancer [for which there are] well-selected samples that have been collected appropriately, a large collection of those samples, and full genome characterization of those samples," she said. "It's a big list of requirements, and not that many cancers right now practically fill that list of requirements."

At a CPTC pre-application meeting last August, several attendees raised questions about the patient samples slated for use in the initiative (PM 08/27/2010). In particular, there were concerns about the fact that samples for the discovery and verification phases of the project would likely have to come from two different sets of patients.

The NCI-funded Cancer Genome Atlas is providing tumor tissue for the discovery stage, along with genome analysis for the tissue, including sequencing, copy number variation, DNA methylation, gene expression, miRNA expression, SNP analysis, and somatic mutations. However, TCGA doesn't have blood from these patients for use in the verification stage of the CPTC initiative, meaning those samples will have to come from a different cohort.

"It's unclear to me [how] the linkage of the tissue analysis [in the discovery stage] with the blood serum analysis in the verification stage … is going to be maintained," George Mason University researcher Emanuel Petricoin told ProteoMonitor at the time.

CPTC director Henry Rodriguez responded to Petricoin's concerns, telling ProteoMonitor that the agency planned to match "patients providing samples for the verification stage to the tumors used in the discovery stage," and citing as an example that "samples used for verification from ovarian cancer patients would involve patients with serous cystadenocarcinoma of the ovary, and exclude mucinous, clear cell, and endometriod ovarian cancers, as the discovery-stage samples involve patients with ovarian serous cystadenocarcinoma."

This question of using different sample sets for the discovery and verification stages emerged at this week's meeting, as well, Giddings said.

Another issue some participants raised is the question of whether post-translational modifications like phosphorylation might have been lost during sample collection. Recent research has suggested that phosphorylation in particular is highly labile and that these modifications can be lost if samples are not quickly flash-frozen after extraction.

However, Giddings added, "no sample set is perfect in all regards, so I think there is a general agreement that the TCGA samples are a good starting point, but they're certainly not a finishing point. The group is still looking at other potential sample sources to supplement what's in the TCGA to address the issues of the matched plasma and also phosphorylation."

"It will probably be the sort of thing where there's a core of TCGA samples that are analyzed and then auxiliary samples from other sources that will be added into the analysis," she said.

One likely source for additional samples would be Matthew Ellis's lab at Washington University, Giddings said, noting that Ellis has developed mouse lines that can maintain growth of certain kinds of tumors, providing researchers tissue for proteomic and genomic analysis.

Although the TCGA samples have not yet been sent out to the groups, work on the project is already ongoing, Giddings said.

"Even before we received the award, we were getting going on some of the discovery angles and trying to get some of those analyses done," she said. She added that, although the project is slated for five years, it will be evaluated by an outside panel at the three-year mark, "so we'll have to have made sufficient progress [in three years]."

In addition to the proteome characterization centers announced this week, the initiative will include a data center and a resource center that have yet to be named.


Have topics you'd like to see covered in ProteoMonitor? Contact the editor at abonislawski [at] genomeweb [.] com.

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