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With Anticipated $65M in Funding, CPTAC's Next Stage Continues Proteogenomic, Translational Push


NEW YORK (GenomeWeb) – With the reissuance late last year of its Clinical Proteomic Tumor Analysis Consortium program, the National Cancer Institute looks to build on the achievements of the initiative's previous two stages while moving the work in an increasingly translational direction.

NCI announced in November that it was soliciting applications for the next stage of the CPTAC project, offering funding for three Proteome Characterization Centers (PCCs), four Proteogenomic Data Analysis Centers (PDACs), and three Proteogenomics Translational Research Centers (PTRCs).

The initiative is slated to run for five years, from 2016 to 2021, with a total of roughly $13 million per year, or $65 million overall, put towards the project, Henry Rodriguez, director of the Office of Cancer Clinical Proteomics Research at NCI, told GenomeWeb. He noted, though, that the final amount of funding would be subject to the annual appropriations process.

The recently announced reissuance continues many of the efforts begun in earlier stages of the project, such as proteomic characterization of a variety of preclinical and clinical tumor samples and work to integrate genomic and proteomic data. It also marks a move towards more translational research, particularly on the part of the three PTRCs, which will aim to use genomic and proteomic data to better understand patient drug response and the development of resistance.

Initially launched in 2006, the NCI initiative has both tracked with and helped drive the progression of the broader proteomics field from an initial focus on technology development toward clinical implementation.

The first stage, Rodriguez noted, which ran from 2006 to 2011, focused largely on "establishing methodologies that demonstrated that high-throughput proteomics approaches could be executed reproducibly and reliably within and across labs." Among the aims of that effort were the standardization of discovery mass spec workflows, the standardization of multiple reaction monitoring-based targeted proteomics workflows, as well assisting in the development of the University of Washington's Skyline software for targeted proteomics, peptide immune-MRM assays, and policies on the open sharing of proteomics data.

Standardized workflows in place, the program moved to its second phase, which is finishing this year, to apply them to analysis of tumor samples. A key aspect of this effort was using samples that had already been genomically characterized by the NCI's Cancer Genome Atlas project, allowing the researchers to integrate proteomic and genomic data.

"The goals were to identify and quantitate proteins that derive from alterations in cancer genomes in order to better understand the proteogenomic complexity of cancer not fully elucidated through genomics," Rodriguez said.

The project also continued work on the assay development and standardization end. Of particular note, Rodriguez added, was the initiative's efforts, in collaboration with partners in academia, industry, and regulatory organizations, to establish practical guidelines for the methods and documentation required to demonstrate that an MRM assay is, in fact, measuring its intended target with the required accuracy.

Indeed, recent years have seen the first clinical implementation of MRM mass spec-based proteomics with, notably, Integrated Diagnostics' launch of its Xpresys Lung proteomic test in 2013 and the initial roll out last year of Sera Prognostics' MRM-based proteomic test for risk of preterm birth. As MRM-based protein assays have moved towards the clinic, though, they have drawn closer scrutiny.

As SISCAPA Assay Technologies CEO Leigh Anderson told GenomeWeb in a 2014 interview, "all of this original proteomics research has moved enough in the direction of [clinical chemistry] that [clinical chemists] are now asking questions that they care about, and not just saying 'OK guys, come back to me when this is really working.'"

And, Rodriguez said this week, concerns about "the criteria used to determine whether targeted mass spec methods work as intended in a given experiment" had slowed "the adoption and dissemination" of these methods.

To address these issues, the consortium of researchers gathered under the umbrella of the second CPTAC initiative developed a set of guidelines spelling out the standards of evidence and analysis required for three tiers of MRM assay – clinical, non-clinical, and comparative. Detailed in a paper published in Molecular & Cellular Proteomics in 2014, the effort, Rodriguez said, marks "a positive step forward by the community that aims to speed up translation[al] research."

That goal of moving toward translation has been made even more explicit in the newest stage of the initiative, where researchers at the participating PTRCs will tackle questions of drug response and resistance.

These centers, Rodriguez said, will "form a multidisciplinary interactive group focusing on applying standardized state-of-the-art proteomic and genomic approaches to clinically relevant research projects."

Building on the proteogenomic analyses done in the second stage of the initiative, these projects "should focus on proteogenomic aspects in elucidating biological mechanisms of response, resistance, and toxicity to therapies in a clinical context," identifying potential predictive biomarkers, he said.

"Genetic information about a particular person's cancer has provided a wealth of knowledge and significant progress in stratifying patients over the last decade, especially in the discovery and development of treatments that target specific genetic abnormalities," Rodriguez said. "However, prediction of drug response and toxicity and the relative rapid acquisition of resistance to such treatments significantly limit their utility and remain a challenge."

The hope, he noted, is that bringing proteome-level information into the process can further inform rational targeting of cancer pathways and, ultimately, improve patient outcomes.

The new stage will also continue and expand the work on basic proteogenomic characterization of different cancer types begun during the second issuance of the initiative.

The program's three PCCs will use their choice of standardized proteomic approaches for proteome-wide characterization of primarily treatment naïve tumors prospectively collected for the project by the NCI. These samples will also undergo genomic characterization.

"Anticipated are five to six cancer types where unanswered questions remain about the molecular biology of the disease," Rodriguez said.