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Clinical Proteomic Tumor Analysis Consortium Background

The discovery that proteins and peptides are "leaked" by tumors into clinically accessible bodily fluids such as blood has led to the possibility of diagnosing cancer at an early stage or monitoring response to treatment by collecting these fluids and testing for the presence of cancer-related biomarkers. Prostate-specific antigen (PSA) and cancer antigen 125 (CA-125) are examples of blood-borne cancer protein biomarkers that are currently being used in the clinic. However, the measurement of individual biomarkers has clinical limitations with respect to both sensitivity and specificity. For this reason, combinations of protein/peptide analytes are under intense investigation as biomarker panels can potentially bring greater sensitivity and specificity to cancer screening than any one analyte alone.

Currently, we do not suffer from a lack of candidate protein biomarkers: Well over 1,000 cancer protein biomarker candidates have been described in the scientific literature over the past decade, and this list continues to grow. However, these studies mostly derive from diverse research groups working independently on available clinical specimens. Consequently, the findings are typically based on an insufficiently low number of samples to provide the adequate statistical power required for rigorous evaluation of the observed protein changes. Relatively few of these candidates have been validated, and even fewer have made it into diagnostic products, suggesting that current biomarker development framework needs to be re-evaluated.

Biomarker Discovery Barriers

There are two key barriers in the early stages of biomarker development, preventing more research discoveries in laboratories from being transferred into the clinic. These include:

1. a limited understanding of the changes in cancer genomes that translate into functional differences at the proteomic level; and
2. insufficient technologies that could be widely applied to reproducibly detect and quantify these aberrant proteomic changes across samples from cancer and control populations.

Additional barriers to the development of cancer protein biomarkers include a lack of technology standardization/optimization; quality affinity reagents; analytical validation considerations (regulatory science) for developers of multiplex proteomics assays; and proper experimental design when performing studies involving clinical samples (e.g., statistical calculations on the number of patients providing biospecimens at each stage of the pipeline to ensure adequate power at the final stage, and sets of biospecimens from appropriate patient cohorts for each stage that reflect the intended use of the assays).  

Addressing Biomarker Pipeline Barriers

Recognizing the need for an evidence-based efficient proteomics pipeline, the National Cancer Institute the Clinical Proteomic Technologies for Cancer initiative launched in 2006. 

The first five years of the initiative focused on removing the technical barriers in proteomic measurements in order to enable the accurate, efficient, and reproducible identification and quantification of proteins to drive clinically-relevant biomarker qualification studies. Prior to the start of the initiative the typical biomarker pipeline focused on blood-based discovery followed by a costly qualification step; this typical pipeline is displayed below, click here for a pdf version of the graphic.

Although discovery efforts on cancer protein biomarkers identify many hundreds to thousands of candidate biomarkers, the initiative investigators recognized that only a few would eventually prove clinically useful.  Therefore, developmental strategies must allow for an efficient testing of many biomarker candidates to identify and verify those few that would be suitable for further large-scale clinical validation.  Addressing this need, researchers designed a two-step workflow for more efficient, timely, and cost-effective development of protein (and peptide) biomarkers prior to clinical qualification studies.  The two steps are outlined below:

• Discovery Step: In the first step of the  process, cancer-specific candidate biomarkers are identified using metrics-driven protein survey technologies that globally interrogate appropriate biospecimens.
• Verification Step: The second step involves the development of targeted, quantitative assays, commonly multiplexed and suitable for the examination of a larger number of biospecimens to ensure appropriate statistical power. These assays are used to examine whether discovered candidate biomarkers are present at a certain concentration which would discriminate disease from control either independently or within groups of other biomarkers. This step provides funneling mechanism to triage candidate biomarkers from discovery to clinical qualification studies.
  

This re-structured pipeline accelerates our ability to move biomarker candidates from discovery to clinical validation.  The restructured pipeline with verification is displayed in the image below, to access a pdf version of the graphic click here.

Connecting Proteomic Technologies with Advances in Cancer Genomics

Recently, significant progress has been made in characterizing and sequencing the genomic alterations in statistically robust numbers of samples from several types of cancer. For example, The Cancer Genome Atlas (TCGA) and other similar efforts are identifying genomic alterations associated with specific cancers (e.g. copy number aberrations, rearrangements, point mutations, epigenomic changes, etc.). The availability of these multi-dimensional data to the scientific community sets the stage for the development of new molecularly targeted cancer interventions. Understanding the comprehensive functional changes in the proteome arising from the genomic alterations and other factors is the next logical step in the development of high-value candidate protein biomarkers. Hence, proteomics can greatly advance the understanding of molecular mechanisms of disease pathology via the analysis of changes in protein expression, their modifications and variations, as well as protein-protein interaction and signaling networks responsible for cellular functions such as apoptosis and oncogenesis.  

Accordingly, the National Cancer Institute's Clinical Proteomic Technologies for Cancer initiative will begin to leverage its analytical outputs in the coming years, through the development of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) composed of Proteome Characterization Centers, Data Center, and Resources Center, to produce a unique continuum that defines the proteins translated from cancer genomes.  The purpose of this integrative approach is to provide the broad scientific community with knowledge that links genotype to proteotype and ultimately phenotype.  Importantly, data sets, analytically validated assays, as well as high quality reagents will be made publicly accessible, which could further be applied by researchers in larger-scale clinical validation studies, such as other NCI programs; e.g., the NCI’s Cancer Therapy Evaluation Program (CTEP), the Early Detection Research Network (EDRN), the Cooperative Groups, and the broad cancer research communities. The primary outputs anticipated from CPTAC will be 1) comprehensive and systematic characterization of proteome from several tumor types for the understanding of cancer biology, and 2) multiplexed quantitative assays for the measurement of candidate protein/peptide biomarkers.