4 OVERVIEW OF THE PROPOSED PROTEOMIC CHARACTERIZATION CENTERS 4 1. DISCOVERY UNIT - BIOMARKER DISCOVERY 11 2. VERIFICATION UNIT - BIOMARKER VERIFICATION 16 A. ADMINISTRATIVE CORE - INTERNAL MANAGEMENT COMMITTEE (IMC) 21 B. TECHNOLOGY/PLATFORM DEVELOPMENT PLAN 22 C. BIOINFORMATICS/BIOSTATISTICS 25 D. HUMAN SAMPLES/STUDIES 28 SPECIAL EMPHASIS PANEL ROSTER DESCRIPTION (provided by applicant): DESCRIPTION (provided by applicant): Biomarkers are unique, detectable signatures of cancer that are vital to early diagnosis and treatment. The causes of many cancers are somatic mutations in critical pathways that serve organ growth and metabolism. For over a decade there have been intense proteomic efforts to find biomarkers with clinical utility. There are thousands of published studies and thousands of candidate biomarkers of unknown value for the management of cancer. With the advent of whole genome sequencing, the challenge and immense potential value of characterizing the cancer proteome the readout of the genome-is unfolding. A new paradigm is therefore emerging -"genome-out" directed proteomics. In this application, we propose a comprehensive, blood-based, protein biomarker discovery and verification pipeline that addresses biomarker discovery by starting where the cancer biology begins: with the driving somatic mutations. In the discovery phase, we will use information about recurrent genomic mutations in cancer (i.e. those that occur with a greater than 5% incidence in any given cancer) that are identified by ongoing whole-genome sequencing efforts to focus our collection and analyses of high-throughput, quantitative proteomic data on samples provided by the NCI CPTC in concert with unique resources such as comprehensively sequenced "human in mouse" breast cancer xenografts. Proteomic analyses will include a multiplicity of high-resolution, current and advanced proteomics methods that can characterize intact proteins, massively complex peptide mixtures and protein modifications to elucidate the proteomic facade of cellular pathways and networks. Bioinformatic tools with rigorous statistical models will be applied to meet the challenges of querying the genome directly with proteomic data (proteogenomics). This will provide the orthogonality that cancer genomics requires to biologically validate copy number alterations, point mutations, splice variants, and the complex biological effects from loss of function mutations and epigenetic changes and translate these findings into actionable clinical information. With this melding of proteomic and genomic knowledge, clinically and biologically informed decisions will be made to select candidate biomarkers. The properties of each candidate will be verified by demonstrating an ability of the biomarker assay to reliably distinguish between blood samples taken from healthy individuals from those accrued from patients with cancer.

Public Health Relevance

While early diagnosis can lead to treatments to eliminate a malignancy before the lethal phase, there are presently few clinically viable diagnostics that can be used as a reliable marker for the need for early intervention. Therefore, the goal of this project is to assist the CPTC in discovering new biomarkers, verifying their clinical applicability, and ultimately, helping translate selected biomarkers into clinical practice to reduce mortality from cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Resource-Related Research Projects--Cooperative Agreements (U24)
Project #
5U24CA160035-03
Application #
8538897
Study Section
Special Emphasis Panel (ZCA1-SRLB-R (J1))
Program Officer
Mesri, Mehdi
Project Start
2011-08-22
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$2,120,962
Indirect Cost
$547,133
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Mertins, Philipp; Yang, Feng; Liu, Tao et al. (2014) Ischemia in tumors induces early and sustained phosphorylation changes in stress kinase pathways but does not affect global protein levels. Mol Cell Proteomics 13:1690-704
Li, Zhijun; Pei, Xin-Hai; Yan, Jun et al. (2014) CUL9 mediates the functions of the 3M complex and ubiquitylates survivin to maintain genome integrity. Mol Cell 54:805-19
Whiteaker, Jeffrey R; Halusa, Goran N; Hoofnagle, Andrew N et al. (2014) CPTAC Assay Portal: a repository of targeted proteomic assays. Nat Methods 11:703-4
Yan, Jun; Yan, Feng; Li, Zhijun et al. (2014) The 3M complex maintains microtubule and genome integrity. Mol Cell 54:791-804
Zhang, Bing; Wang, Jing; Wang, Xiaojing et al. (2014) Proteogenomic characterization of human colon and rectal cancer. Nature 513:382-7
Carr, Steven A; Abbatiello, Susan E; Ackermann, Bradley L et al. (2014) Targeted peptide measurements in biology and medicine: best practices for mass spectrometry-based assay development using a fit-for-purpose approach. Mol Cell Proteomics 13:907-17
Bai, Chen; Tang, Siwei; Bai, Chen et al. (2014) Quantitative proteomic dissection of a native 14-3-3? interacting protein complex associated with hepatocellular carcinoma. Amino Acids 46:841-52
Ellis, Matthew J; Gillette, Michael; Carr, Steven A et al. (2013) Connecting genomic alterations to cancer biology with proteomics: the NCI Clinical Proteomic Tumor Analysis Consortium. Cancer Discov 3:1108-12
Khatun, Jainab; Yu, Yanbao; Wrobel, John A et al. (2013) Whole human genome proteogenomic mapping for ENCODE cell line data: identifying protein-coding regions. BMC Genomics 14:141
Ellis, Matthew J (2013) Mutational analysis of breast cancer: guiding personalized treatments. Breast 22 Suppl 2:S19-21

Showing the most recent 10 out of 17 publications