December, 2005 (Vol. 1, No. 6) Scientific Updates Recent Publications Collaborative Software Administrative Updates Biomarker Team Spotlight Key Web Pages at FHCRC

Dear ICBC Team Members:

We are trying to get many activities scheduled for the New Year, including.

• Steering Committee Conference Call (February)
• Explore options for software/technology to allow easier consortium interactions
• Establish Working Groups goals for next year
• Schedule Steering Committee videoconference site visits with each team (please see Administrative Updates for more information on the videoconference site visits)

We held a small conference call on the glycocapture project and Dr. Aebersold is writing up a document that will be distributed to the consortium in a separate e-mail.

We would like to publish updates from each of the working groups in the March edition of the newsletter.

Best regards,

Lee Hartwell
President and Director
Fred Hutchinson Cancer Research Center

Candidate Biomarker Database Completed
By Dr. Malu Polanski

As the International Biomarker Discovery Consortium teams prepare to tackle the enormous task of identifying and cataloging biomarkers for multiple types of cancer, each team would like to know how their experimentally obtained datasets compare with the present literature on human cancer biomarkers. Since no such generalized database of cancer markers existed, all teams will be glad to know that at the Plasma Proteome Institute in Washington, DC, USA, Dr. Leigh Anderson and I have produced the beginnings of such a biomarker database and will be submitting this database for publication within the next few months

We have begun to compile and prioritize a database of candidate biomarkers reported to be differentially expressed for any form of cancer either at the protein or nucleic acid level. In order to focus on the most promising clinical candidates, we restricted the database to biomarkers demonstrated in studies involving primary human tissue i.e. biomarkers that were restricted to animal, cell culture systems, or single patient studies were not included.

To date this database consists of 1261 proteins categorized by tissue of discovery and at least one cancer indication. The candidates include proteins involved in oncogenesis, angiogenesis, development, differentiation, proliferation, apoptosis, hematopoiesis, immune and hormonal responses, cell signaling, nucleotide function, hydrolysis, cellular homing, cell cycle and structure, the acute phase response, and hormonal control. Two hundred and seventy four of these biomarkers have already been detected in plasma. We hypothesized that the protein version of most, if not all of the others should also be detectable in blood plasma, ultimately allowing for their clinical use in patient screening, diagnosis or follow-up. This database therefore presents a repository of candidate plasma biomarkers that could be useful not only as a catalogue against which to confirm new results but also that could be useful in early cancer detection and monitoring given sufficiently sensitive specific assays.

Of these 1261 proteins only 41 are used in some clinical sense and even fewer have FDA approved assays. For the proteins in the list with known plasma concentrations we estimate that 86% would be missed by most conventional proteomics platforms, while 48% would be missed by high-end proteomics platforms with extensive multi-dimensional fractionation. Therefore the need exists both for the continued compilation of biomarkers discovered by all methodologies as well as a systematic testing of all biomarkers found both singly and as members of biomarker panels. Recently multiple investigators have demonstrated greatly increased sensitivity and specificity of panels over individual markers. For the present, the only way that many of these proteins can be detected and validated in plasma is by specific assays: i.e., by targeted proteomics. For this purpose the top 260 candidates have been prioritized and will be the focus of further studies.

This database hopefully presents the beginning of systematic collection and large-scale validation of candidate cancer biomarkers, a process that could fill the gap currently existing between basic research discoveries and FDA approval of clinical diagnostics.

Our work on the cancer candidate biomarker database development was supported by a subcontract from the National Cancer Institute.

In addition, my colleague Dr. Anderson has published extensively on the plasma proteome in general (J Proteome Res 3:235-44, 2004; Circulation 109:1697-703, 2004; Mol Cell Proteomics 3(4):311-26, 2004; (Current Opin in Mol. Ther. 5:250-257, 2003;Mol Cell Proteomics 1(11):845-67, 2002) and the cardiovascular disease proteome in particular (J Physiol 563(1):23-60, 2005).

Rauch A, Bellew M, Eng J, Fitzgibbon M, Holzman T, Hussey P, Igra M, Maclean B, Lin CW, Detter A, Fang R, Faca V, Gafken P, Zhang H, Whiteaker J, States D, Hanash S, Paulovich A, McIntosh M. Computational Proteomics Analysis System (CPAS): An Extensible, Open-source Analytic System for Evaluating and Publishing Proteomic Data and High throughput Biological Experiments. J Proteome Res 2005, ASAP Web Release 8 Dec

We recently saw a demo for Sharepoint software—does anyone in the Consortium have experience with Sharepoint or any other collaborative software system? We are interested in feedback or suggestions on ways to encourage more real-time interactions between teams through message boards, chat rooms, etc.

Videoconference Site Visit Update

We are planning to have the consortium's initial videoconference in February to allow more focused dialogue between individual teams and Steering Committee specialists. Fred Hutchinson Cancer Research Center has contracted a consultant to assist with these videoconferences. In early January our video consultant, Tom Bigliani at SPL Integrated Solutions, will be contacting many of you to assess your site's video conferencing capabilities. To insure the success of these calls, please respond promptly to Tom Bigliani when he contacts you. Also, if you have not yet provided us with a technical contact person at your site, please e-mail that information to me at kkreizen@fhcrc.org. Thank you so much for your assistance.

Brief Description of Project:

Annually, hepatocellular carcinoma (HCC) or hepatoma affects more than one million people globally with five-year mortality exceeding 95%. More than half of these cases are in China. With a three-fold increase in incidence in the USA over the past decade, HCC should be viewed as a major health problem for which there is a compelling need for early detection and better treatments. The therapies for treatment of small HCC tumors that offer great hope of controlling this disease have emerged. One of the major impediments to eradicating HCC has been the inability to diagnose these tumors at an early stage. The combination of routine periodic ultrasonography with the measurement of a single tumor marker, alpha-fetoprotein (AFP), has markedly improved early diagnosis. This has prompted a surge in interest in early detection as new tumor markers have been proposed for HCC.

The goal of the HCC Biomarker Discovery Consortium is to 1) identify biomarkers (proteins) that reveal the presence of HBV (hepatitis B virus)-related HCC in a body fluid test and 2) identify HCC metastasis-related biomarkers. A test for early detection would save countless lives, as less than one in five patients with HCC have the fortune to be diagnosed at an early stage, thereby permitting a curative approach to be started. These HCC cancer biomarkers will also be used routinely for population screening, prognosis, monitoring of therapy, and prediction of therapeutic response.

Four main strategies support the Consortium plans, including:

Technology platform - an integrated and high-throughput working platform for investigating the transcriptome (transcript array analysis), proteome (protein expression profile, differential expression profile, PTM profile, and antibodies generation), and metabolome (metabolites profile) including specific strategies for protein pre-fractionation and enrichment prior to mass spectrometric analysis;

HCC biomarker discovery pipeline - a comparative and complementary analysis of HBV-related HCC using human samples including sera/plasma, urine, tumor interstitial fluid, tumor tissue as well as cell lines and animal models; a biomarker discovery pipeline employing immunologic strategies to find biomarkers from tumors as well as the host's own immune response to disease, and thereby identifying two classes of biomarkers that may complement each other in a diagnostic panel;

Antibody-based platform - development of novel analytical techniques such as immunologic assays and monoclonal antibody technology for HCC biomarker discovery;

Bioinformatics platform - application of data standards, data management system, and database systems support for biomarker discovery and validation work.

Team Members and Expertise:

Yun CAI

Shujun CHENG, M.D.

Jianen GAO

Yuan GAO

Fuchu HE, Ph.D. (Biomarker Team Co-PI)
[hefc@nic.bmi.ac.cn;hefc@cnhupo.org]

Ying JIANG

Jianqi LI

Xiaohong QIAN, Ph.D. (Biomarker Team Co-PI)

Qihong SUN, Ph.D. (Biomarker Team Co-PI)
[qihongs@vip.sina.com]

Wei SUN

Baocai XING

Jinju YANG

Xiao YANG

Wantao YING

Yangjun ZHANG

Xiaohang ZHAO

Yunping ZHU

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