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Clinical Proteomic Technologies for Cancer (CPTC) 2007 Annual Meeting

Executive Summary

Purpose of the CPTC Annual Meeting
The Clinical Proteomic Technologies for Cancer (CPTC) initiative was established by the National Cancer Institute (NCI) with the ultimate objective of building the foundation of technologies, data, reagents and reference materials, analysis systems, and infrastructure needed to systematically advance our understanding of protein biology in cancer and accelerate discovery research and its clinical applications. NCI hosted the first CPTC Annual Meeting on October 24-25, 2007, to report on and review the progress made during the first year of the initiative.

CPTC currently consists of two broad programs: the Mouse Proteomic Technologies Initiative (MPTI) and the Clinical Proteomic Technologies Initiative (CPTI). The CPTI comprises three components: Advanced Proteomic Platforms and Computational Sciences, the Proteomic Reagents and Resource Core, and the five Clinical Proteomic Technology Assessment for Cancer (CPTAC) Centers of Excellence. The MPTI, which is largely complete, was focused on the mouse as a model for proteomic technology development and cancer etiology.

In his opening remarks, NCI Director John Niederhuber, M.D., noted that cancer is most curable when detected at an early stage. However, better methodologies are needed for early detection and also to monitor response to interventions. He next emphasized that while proteomics represents an essential component of this vision, it will require technology advances and optimization similar to those taking place in genomics, and the open collaboration of investigators from multiple disciplines, including the physical sciences, engineering, and cancer biology.

NCI patient cancer advocate, Ann McNeil, RN, further emphasized the importance of NCI’s commitment to this area, as cancer patients are engaged in an emotional and logistic battle; with the disease imposing a burden that affects all aspects of quality of life.

NCI Deputy Director, Anna Barker, Ph.D., further noted that molecular diagnostics - those based on "signatures" at the DNA, RNA, protein, and epigenomic levels - hold great promise for impacting every phase of cancer diagnosis and treatment. Standardization, however, remains a key barrier to the development of molecular diagnostics, along with adequate technology platforms, robust reagents, pre-competitive datasets, intellectual property approaches, bioinformatics tools, defined regulatory pathways, partnerships and collaborative teams, and end-to-end systems.

With these issues in mind, CPTC was designed to ultimately provide:

  • Connected and coordinated core technology laboratories to optimize current technology platforms and methods
  • Shared high-quality biospecimen and reagent resources designed for proteomics research
  • High-throughput instrumentation
  • Enhanced development of advanced technologies (multiplexed technologies)
  • Development of standards
  • Data management platforms and knowledge creation
  • Connected teams of a coordinated system to support national/international scale cancer proteomics

During the annual meeting, CPTC members set out to discuss the goals, achievements, challenges, and lessons learned over the previous year, specifically in the CPTI. Lead investigators of numerous CPTI-supported programs presented updates on their respective research and development activities.

The CPTAC Sites Are Developing and Optimizing Technologies and Standards that will Advance Group Efforts in Proteomics-Based Cancer Research
Based on the results of the initial NCI-sponsored CPTAC meeting (held in 2006), efforts have been undertaken to develop common reagents, biospecimen protocols, and data analysis procedures. Standards (e.g., universal internal standards) are a key component in experiments conducted by groups spread across multiple institutions, allowing effective interchange and common interpretation of data regardless of where an experiment is conducted. Delivering to the cancer community ways to address sources of variability for the detection of analytes/candidates at various detection limits, will accelerate the implementation of proteomic analysis technology in monitoring cancer-relevant proteins and peptides in clinical samples. To address standardization issues within CPTI, a set of working groups was established among the CPTAC sites focused on discovery, validation, verification, yeast and plasma issues, selection and production of protein standards, data analysis, and biospecimens. At the annual meeting, the working groups gave reports on:

  • Unbiased discovery studies in spiked protein and yeast lysate matrixes
  • Validation studies using multiple reaction monitoring (MRM) techniques
  • Research into serum peptide profiling ("peptidomics") using magnetic silica-based microparticle beads
  • Diagnostic protein discovery strategies based on measurements of cell surface carbohydrates, alternative splicing events, and post-translational modifications
  • Experimental and data analysis standardization and optimization for shotgun proteomics
  • Development and validation of technologies for protein separation
  • Verification and measurement of candidate biomarkers via targeted mass spectroscopy (MS) and antibody enrichment

Particular effort was made during these studies to identify and minimize sources of inter-experimental and inter-laboratory variability and develop techniques and procedures that could be standardized for use across multiple centers.

International Leaders in Proteomic Research Discussed the Challenges of Conducting Collaborative Research across Multiple Centers
As part of the annual meeting, a panel including directors of proteomic research consortia from several countries (i.e., Sweden, South Korea, Canada) and members of the US Food and Drug Administration (US FDA) convened to discuss the following questions:

  • What is the most significant barrier preventing biomarker discoveries from translating into clinical applications and what efforts are key to overcoming this barrier?
  • What role and implications do you see for standards in discovery, verification, and validation proteomics?
  • What specific projects in proteomics can best be accomplished through multi-institutional collaborations?

The Proteomic Reagents and Resource Core is a Virtual Central Standards Repository for CPTI
The lack of high-quality, well-characterized protein capture reagents (e.g., antibodies), as well as standard operating procedures (SOPs), standard peptide or protein mixtures, and other reagents, remains a significant barrier in proteomic research. In attempt to address these challenges, CPTC has established the Proteomic Reagents and Resource Core, which serves as a central resource for:

  • Developing well-characterized reagents (antigens and antibodies – part of the program’s Antibody Characterization Pipeline)
  • Developing appropriate SOPs
  • Providing a publicly-available database (web site) on reagent performance

An NCI-sponsored Proteomic Technologies Reagents Resource workshop, held in December 2005, laid the groundwork enabling the Resource to enhance the availability of antigens and antibodies for the proteomics research community in ways that minimize intellectual property barriers, facilitate microvolume distribution of reagents, and make resources available for multiplex affinity platform development. Currently, the resource is working with multiple laboratories to produce, characterize, and distribute antibodies against cancer-related protein candidates.

The NCI Clinical Proteomics Informatics Strategy is Designed to Improve the Reliability of Proteomics Data
The NCI seeks to develop informatics resources that create better and faster tools that are accessible to laboratories engaged in proteomics research. CPTC is working the NCI Center for Biomedical Informatics and Information Technology and other organizations to develop and implement tools such as the Clinical Proteomics Analysis System (CPAS), Tranche, and others. A series of workshops has been planned to discuss and engage the community in tool development, use, and distribution.

The Advanced Proteomic Platforms and Computational Sciences Sites Are Incubating Powerful New Technologies for Cancer Proteomic Research
Data and updates were presented at the annual meeting from 15 projects currently sponsored by CPTC under the Advanced Proteomic Platforms and Computations Sciences initiative. This group of projects is intended to develop innovative new tools, reagents, and technologies for protein/peptide measurement. Reports included updates on:

  • Biomarker discovery and validation platform development
  • Software, procedures, and algorithms for protein detection and data analysis
  • Systems for investigating proteins that have undergone post-translational modifications (e.g., phosphorylation, ubiquitination) or sequence alterations (e.g., codon polymorphisms, alternative splicing)
  • Monoclonal antibody production
  • Technologies for the detection and investigation of protein profiles and patterns