Prior to the current Clinical Proteomic Tumor Analysis Consortium (CPTAC), previously funded initiatives associated with clinical proteomics research included:
Clinical Proteomic Tumor Analysis Consortium 3 (CPTAC 3)
The Clinical Proteomic Tumor Analysis Consortium (CPTAC) program began in 2006 as a part of the Clinical Proteomic Technologies for Cancer initiative (CPTC) at the NCI (see below), the purpose of which was to develop standardized proteomic assays and workflows to ensure analytical reproducibility of proteomic measurements (Rigor & Reproducibility), in order to complement genomic and transcriptomic analyses. To begin to apply these technical outputs, CPTAC was launched in 2011 (RFA-CA-10-016; commonly referred to as CPTAC 2) as a pilot program to utilize the developed state-of-the-art standardized proteomic workflows on genomically-characterized tumors (such as those from The Cancer Genome Atlas - TCGA) to add an additional layer of functional biology to cancer. The goal was to determine if additional biological insights would be identified – biology that is difficult or impossible to obtain solely through genomics approaches.
With the success in the prior issuance on proteomic measurements adding an additional dimension to tumor biology, in 2016 NCI expanded CPTAC’s infrastructure to include tissue collection, genomic and proteomic characterization and analysis, and resource dissemination (RFA-CA-15-021, RFA-CA-15-022, RFA-CA-15-023; commonly known as CPTAC 3). The CPTAC 3 program was composed of Proteome Characterization Centers (PCCs), Proteogenomic Data Analysis Centers (PGDACs) and Proteogenomic Translational Research Centers (PTRCs). PCCs generated mass spectrometry-based data of NCI provided biospecimens (genomically characterized) using high throughput analytically validated proteomic technologies, PGDACs integrated, visualized and analyzed CPTAC data by collaborating with PCCs and PTRCs, and PTRCs applied proteogenomic approaches to clinically relevant research projects in collaboration with NCI-sponsored clinical trials. The overarching goals of the CPTAC 3 were (i) to increase our understanding of cancer by comprehensively characterizing tumors (proteomically and genomically), (ii) to continue to produce public resources (data, assays, images, reagents) that catalyze “hypothesis-driven science,” and (iii) to support clinical research projects [using both sets of omics] that address mechanisms of treatment response, resistance, or toxicity. In the Tumor Characterization Program, CPTAC extended deep comprehensive proteogenomic analysis to new cancer types (treatment-naïve tumors and normal adjacent tissues prospectively collected using strict standardized protocols optimized for proteomic and genomic analyses) and publicly released all available corresponding data (RNA, DNA, protein, and medical images), assays and reagents. In the Translational Research Program, CPTAC, in collaboration with NCI-sponsored clinical trials, supported clinically relevant research projects (in collaboration with clinical researchers and use human biospecimens from clinical trials), to facilitate a rational approach to target cancer related pathways and improve outcomes for patients with cancer. The Translational Research Program focused on breast cancer, ovarian cancer, and acute myeloid leukemia.
Key Research Outputs include:
The program has demonstrated leadership towards the integration of proteomic and genomic (proteogenomics) workflows (analytical and computational) into cancer research and clinical trials, to accelerate the development of new cancer diagnostics and therapeutics to advance patient care.
- Coordinated with the FDA on a Public Workshop on Liquid Chromatography-Mass Spectrometry (LC-MS) in the Clinic.
- Coordinated with the Clinical and Laboratory Standards Institute (CLSI) on the development of Consensus Guidance Document (CLSI C64-A), on the measurement of peptides using a mass spectrometer.
- Developed CLIA Certified CPTAC Assays/Labs (Clinical Reference Laboratories in North America) and affiliated International Partners for Thyroglobulin targeted mass spec assay and HER-2 targeted mass spec assay.
- Developed NCI’s Proteomic Data Commons (PDC) in coordination with the Center for Biomedical Informatics and Information Technology (CBIIT) to share proteomic/proteogenomic data in a common location that satisfies findability, accessibility, interoperability, and reusability. The PDC is NCI's largest public repository of proteogenomic comprehensive tumor data.
- Developed a CPTAC DREAM Proteogenomics Big Data Crowdsourced Computational Challenge for extracting information from cancer proteomes and linking those data to genomic and transcriptomic information.
- Partnered with the FDA, in coordination with the DREAM Challenges, on the development of a Crowdsourced Multiomics Sample Mislabeling Big Data Challenge.
- Coordinated with the Department of Defense and Veterans Administration to establish the cancer moonshot APOLLO program.
- Coordinated with international organizations to establish the International Cancer Proteogenome Consortium (ICPC), to encourage cooperation and investments among nations and institutions with an interest in proteogenomics.
- Released a public curation of CPTAC proteogenomic computational tools developed and/or utilized by CPTAC for processing and analysis of proteogenomic data.
- Flagship proteogenomic cancer studies:
- AML study – Leukemia 2018, PMID: 29743719.
- Ovarian cancer study – British J of Cancer 2018, PMID:30385821.
- Clear cell renal cell carcinoma study – Cell 2019, PMID: 31675502.
- Colorectal cancer study – Cell 2019, PMID: 31031003.
- Breast cancer study – Nat Commun. 2020, PMID: 31988290.
- Uterine corpus endometrial carcinoma study – Cell 2020, PMID: 32059776.
- Lung adenocarcinoma study – Cell 2020, PMID: 32649874.
- Ovarian cancer study – Cell Rep. 2020, PMID: 33086064.
- Ovarian cancer study – Cell Rep. 2020, PMID: 32529193.
- Pediatric glioblastoma study – Cell 2020, PMID 33242424. (coordination with NIH’s Gabriella Miller Kids First Pediatric Research Program).
- Breast cancer study – Cell 2020, PMID 33212010.
- Adult glioblastoma study – Cancer Cell 2021, PMID: 33577785.
- AML study – Cancer Cell 2021, PMID: 34171263.
- Head and neck squamous cell carcinoma study – Cancer Cell 2021, PMID: 33417831.
- Lung squamous cell carcinoma study – Cell 2021, PMID: 34358469.
- Pancreatic ductal adenocarcinoma study – Cell 2021, PMID: 34534465.
Clinical Proteomic Tumor Analysis Consortium 2 (CPTAC 2)
The CPTAC 2 program was composed of five Proteome Characterization Centers (PCCs) with expertise in proteomics, genomics, cancer biology, oncology and clinical chemistry that perform coordinated research projects to comprehensively characterize and analyze cancer specimens selected for study. CPTAC’s “proteogenomics” approach (comprehensive proteomics combined with genomics), successfully demonstrated the scientific benefits of integrating proteomics with genomics to produce a more unified understanding of cancer biology and possibly therapeutic interventions for patients, while creating resources that are widely used by the global cancer community.
Key Research Outputs include:
- Understanding tumor preanalytical variables to help refine tumor collection protocols optimized for proteomic analyses by minimizing preanalytical variables such as ischemic time, etc. (Mol Cell Proteomics 2014; PMID 24719451).
- Development of a Comparative Reference Material (CompRef) for proteomics labs to benchmark analytical drift over the course of an analysis (J Proteome Res. 2016, PMID 26653538).
- Flagship proteogenomic cancer studies:
CPTAC’s proteogenomic approach to science created open community resources that are now some of the most widely used by the global cancer community. Raw data files are released to the public before CPTAC’s flagship publications, while targeted protein assays are developed using a fit-for-purpose framework established in coordination with the Food and Drug Administration (FDA) and American Association for Clinical Chemistry (AACC).
Clinical Proteomic Technologies for Cancer Initiative (CPTC)
The Clinical Proteomic Technologies for Cancer Initiative (RFA-CA-07-012 and RFA-CA-07-005), launched in 2006, was developed to address the pre-analytical and analytical variability issues that are major barriers to the field of proteomics. These barriers were: (1) experimental design; (2) technological and technical aspects of protein identification; (3) variability related to biospecimens collection; (4) the processes of data acquisition, analysis, and reporting; (5) the lack of reproducible proteomic technologies; and (6) the lack of highly characterized and standardized reagents. The initiative was composed of three integrated programs that worked together to overcome these barriers:
- Clinical Proteomic Technology Assessment for Cancer network: Network of 5 multidisciplinary teams that collaborated on research projects to increase the understanding of experimental and analytical sources of error for existing technologies.
- Advanced Proteomic Platforms and Computational Sciences: Team of individual investigators that developed new analytical tools, technology, and software to improve the accuracy and reproducibility of proteomic measurement.
- Proteomic Reagents and Resources component: Provided high quality, well-characterized reagents (antibodies), data, and standard reference materials for the research community.
Key Research Outputs include:
The program has showed the effectiveness of a multidisciplinary team approach to address the issues of variability in proteomic technologies. Program achievement highlights include:
- Standardization of mass spectrometry (MS) methodologies for untargeted protein analyses (discovery proteomics - Rigor & Reproducibility).
- Standardization of multiple reaction monitoring (MRM) mass spectrometry in targeted protein analyses (targeted proteomics - Reproducibility & Transferability).
- Open-source computational tool (Skyline) for designing targeted mass spec assays.
- Adoption of a MRM assay for thyroglobulin by clinical reference laboratories, development of an open-source computational tool (Skyline) for designing MRM assays that is supported by major instrument vendors.
- Development of mock 510(k) device clearance documents using targeted proteomic platforms in coordination with the Food and Drug Administration (FDA) and the American Association for Clinical Chemistry (AACC).
- Development of open data sharing policies in proteomics that are supported by peer-reviewed journals (Amsterdam Principles). Documents 1 and 2.
Additional outputs from this initiative include:
- Reference Materials: In collaboration with the National Institute of Standards and Technology (NIST), a soluble yeast protein extract reference material and software metrics tool (to monitor the performance of liquid chromatography-mass spectrometry systems) were developed. This, along with its publicly available reference datasets, provides a foundation for laboratories to benchmark their own performance, improve upon current methods, and evaluate new for technologies.
- Biospecimen Samples: The CPTAC network collected clinical plasma samples were collected from approximately 1,700 patients undergoing breast biopsies. Additionally, there is a second collection of approximately 200 breast cancer patients with multiples time points per patient collected after completion of treatment. Accompanying each sample is a set of clinical patient data covering the demographic, medical history, pathology report, and sample processing variables. In addition, SOPs for the collection, processing and storage of plasma samples were developed and available upon request.
- Community Resources: Well-characterized renewable antibody reagents with data from standardized processes were made publicly available to the research community online at the Antibody Portal.
More information related to the reconstructed biomarker pipeline and other key research outputs are available in the 2009 CPTC Annual Report, to download click here.
Mouse Proteomic Technologies Initiative
Mouse models of human cancer offer many opportunities to optimize procedures for profiling major human cancers. The Mouse Proteomic Technologies Initiative, designed to use these animal models to develop and standardize technologies to help improve the accurate measurement of proteins and peptides linked to cancer processes. Launched in 2004 with funding to two consortia, the program was designed as a multidisciplinary and collaborative team science approach towards the development of standard tools and resources needed to accelerate protein biomarker discovery. The goals of the initiative were to use mouse models to: 1) standardize methods for protein and peptide detection and analysis; 2) develop metrics for benchmarking performance and supporting reagents for promising technologies; 3) identify or characterize new biomarkers associated with cancer processes in mouse models of human cancer; 4) enhance current technologies for the analysis of proteins and peptides in biological fluids; 5) refine and standardize methods of specimen preparation and develop specimen reference standards; 6) design common data elements and algorithms to facilitate data sharing amongst different laboratories; and lastly 7) improve detection capabilities associated with current technologies, including sensitivity and resolution.
Key Research Outputs include:
The Mouse Model consortium produced several advances in the field of proteomics including a number of research tools available to the cancer research community. These tools include: Computational Proteomics Analysis System (CPAS): An open-source, web-based proteomics data management software suite that combines laboratory information management systems and informatics modules for high-throughput liquid chromatography/tandem mass spectrometry (LC/MS/MS) experiments. CPAS enables the cancer proteomics community to store, analyze, and share clinical proteomics data.
The Initiative funded two consortia of laboratories: the "Eastern Consortium" based at the University of Michigan (Ann Arbor, MI) and the "Western Consortium" based at the Fred Hutchinson Cancer Research Center (Seattle, WA), to develop and standardize technologies used to identify proteins and peptides in complex mixtures.
The "Eastern Consortium" based at the University of Michigan (Ann Arbor, MI) included:
- Dana-Farber Cancer Institute (Boston, MA)
- Fred Hutchinson Cancer Research Center (Seattle, WA)
- Harvard-Partners Center for Genetics and Genomics (Cambridge, MA)
- Massachusetts Institute of Technology (Cambridge, MA)
- Memorial Sloan-Kettering Cancer Center (New York, NY)
- Van Andel Research Institute (Grand Rapids, MI)
The "Western Consortium" based at the Fred Hutchinson Cancer Research Center (Seattle, WA) included:
- Institute for Systems Biology (Seattle, WA)
- Pacific Northwest National Laboratory (Richland, WA)
- Plasma Proteome Institute (Washington, DC)