Breast – Fred Hutchinson Cancer Research Center (Coordinating Center)

Brief Description of Project:

"Improving Early Detection of Breast Cancer with a Blood Test" is a multi-institutional research project to identify biomarkers (proteins) that reveal the presence of breast cancer in a blood test and then to determine which are effective markers of early disease and which of therapeutic response. Multiple nationally-recognized laboratories expert in proteomics technology have been brought together, each of which will take a different and complementary approach to the discovery process. This will be the first study of its kind conducted across expert Consortium laboratories sharing methodologies. In addition, the sharing of common specimen samples, data, and data analysis tools will allow researchers to extend their knowledge to one another and ultimately to their colleagues in the scientific community.

The basic strategy of the Consortium will be to employ two discovery modes. One is a candidate approach which first identifies the most likely disease-specific proteins in the tumor or its proximal fluids from existing scientific literature, then evaluates the blood of patients compared to normal individuals for the presence/absence of these candidates. Since the candidates are likely to be present in blood at very low concentration, a suite of techniques to identify very low abundance proteins suspected of being useful diagnostic agents will be used. These techniques include glycopeptide enrichment, antibody enrichment, and abundant serum protein depletion followed by mass spectrometry. A second approach is to compare directly the blood of cancer patients with that of normal controls using unique instrumentation and techniques developed by Consortium members including intact protein analysis system (IPAS) and visible isotope-coded affinity tags (VICAT). Biomarkers diagnostic of cancer will be identified and quantitated by these methods.

The central focus of this project is to develop and apply high throughput methods for the detection, identification, and validation of features (potential protein or peptide biomarkers or signatures) from nipple aspirate fluid (NAF), tumor tissue, and blood plasma that are suitable for routine screening leading to the early detection of breast cancer. The substantial complexity and vast dynamic range of protein abundance in biological fluids present a formidable challenge for comprehensive protein analysis, necessitating integration of multiple technologies to achieve comprehensive high-resolution and high-sensitivity analysis. The Consortium will tap the enormous combined expertise of researchers in the fields of proteomics, informatics, and clinical breast cancer care and direct it towards the critical goal of detecting breast cancer early.

Team Members and Expertise:

Ruedi AEBERSOLD, Ph.D. (Institute for Systems Biology) [ruedi@systemsbiology.org]
Dr. Aebersold is a Professor and Co-Founder of the Institute for Systems Biology. He is one of the pioneers in the field of proteomics and is known for developing a series of methods that have found wide application in analytical protein chemistry and proteomics. Most recently, his group developed a method for the rapid identification and accurate quantification of cellular proteins, i.e., for the generation of cellular "protein profiles." The method is based on a new class of reagents termed Isotope Coded Affinity Tags, or ICAT reagents, and mass spectrometry.

Gordon A. ANDERSON (Battelle/Pacific Northwest National Laboratory)
Dr. Anderson has over 20 years of experience in the development of instrument control and data acquisition systems. Mr. Anderson will be responsible for all electronics, automation, and software engineering aspects of the project. Mr. Anderson received his A.S. degree in Electronics Technology at Columbia Basin College in Pasco Washington and his B.S. degree in Electrical Engineering at Washington State University.

David G. CAMP, II, Ph.D. (Battelle/Pacific Northwest National Laboratory) [dave.camp@pnl.gov]
Dr. Camp is a biochemist with a background in protein isolation, purification, characterization, enzymatic digestion, peptide fractionation, stable-isotope labeling methods, and nano-sample handling. Dr. Camp received his chemistry B.S. at Albertson's College of Idaho and his Chemistry Ph.D. at the University of Montana, Missoula.

Steven CARR, Ph.D. (The Broad Institute) [scarr@broad.mit.edu]
Dr. Carr leads the Proteomics and Biomarker Discovery efforts at the Broad Institute of MIT and Harvard. Dr. Carr's research for the last 25 years has focused on applying and developing proteomics methods to characterize protein pathways, understanding the mechanism of action of drug candidates, defining biomarkers of disease and drug effect, and building an understanding of protein targets and their roles in disease. He has over 125 peer-reviewed publications on development and use of proteomics and biological mass spectrometry.

Ronald A. DEPINHO, M.D. (Dana Farber Cancer Institute) [ron_depinho@dfci.harvard.edu]
Dr. Depinho is a professor of Medicine and Genetics, Harvard Medical School at the Dana Farber Cancer Institute. He received his M.D. at Albert Einstein College of Medicine. Dr. DePinho has developed a program to understand the role of telomerase in cancer, development, and aging, and how telomere dynamics interrelate to DNA damage and recombination pathways.

Francisco ESTEVA, M.D., Ph.D. (MD Anderson Cancer Center) [festeva@mdanderson.org]
Dr. Esteva is an Associate Professor in the Depts. of Breast Medical Oncology and of Molecular and Cellular Oncology at M.D. Anderson Cancer Center. He is the Director of the Breast Cancer Translational Research Laboratory at MD Anderson. Dr. Esteva received his M.D. in 1988 and a Ph.D. in Medical Sciences in 2001, both degrees from the University of Zaragoza School of Medicine in Zaragoza, Spain. He was an Intern in Internal Medicine at Cooper Hospital/University Medical Center in Camden, New Jersey from 1991-1992 and a Resident in Internal Medicine there from 1992-1994. This was followed by a fellowship in Medical Oncology at Georgetown University Medical Center from 1994-1996. His clinical interests concern the use of biologic therapies in breast cancer and his research focuses on biomarkers as prognostic and/or predictive factors in breast cancer and experimental therapeutics.

Michael GILLETTE, M.D., Ph.D. (The Broad Institute) [gillette@broad.mit.edu]
Dr. Gillette is an Instructor at the Dana Farber Cancer Institute and Harvard Medical School, as well as a Research Fellow at the Broad Institute/MIT. He is a research scientist with expertise in application and development of MS-pattern-based biomarker discovery. Dr. Gillette also practices critical care medicine at Massachusetts General Hospital part-time during the year. Dr. Gillette brings a blend of clinical knowledge and current practice, together with laboratory skills and knowledge of proteomics to this program.

Todd R. GOLUB, M.D. (The Broad Institute) [golub@broad.mit.edu]
Dr. Golub leads the Cancer Genomics Program at the MIT/Broad Institute and is the Charles A. Dana Investigator in Human Cancer Genetics at the Dana-Farber Cancer Institute, as well as an Associate Professor of Pediatrics at Harvard Medical School and a Howard Hughes Medical Institute (HHMI) Investigator. Dr. Golub's work focuses on using the human genome to understand the biological and clinical challenges facing cancer medicine and he oversees all aspects of microarray-based gene expression projects at the Institute. Dr. Golub is the recipient of several awards, including the Daland Prize of the American Philosophical Society, Discover Magazine's Inventor of the Year (Health Category), and the Cornelius P. Rhoads Award of the American Association for Cancer Research.

Sam HANASH, Ph.D. (Fred Hutchinson Cancer Research Center) [shanash@fhcrc.org]
Dr. Hanash is the leader of the newly developed Molecular Diagnostics program at FHCRC. Dr. Hanash's interests and expertise focus on the development and application of integrated approaches to the molecular profiling of cancer, with a particular emphasis on proteomics. Dr Hanash's Ph.D. training is in Human Genetics with clinical training in Pediatric Oncology. He has been program PI for multi-investigator projects funded by the NCI, including program projects and, most recently, was PI for an NCI-funded Director's Challenge program, which focused on molecular profiling of lung, colon and ovarian cancer. He is also PI on an NCI-funded Cancer Biomarker Development program which focuses on the application of proteomics to the discovery of protein markers for the early diagnosis of lung and GI cancers.

Lee HARTWELL, Ph.D. (Fred Hutchinson Cancer Research Center—Biomarker Team PI) [lhartwell@fhcrc.org]
Dr. Hartwell is President and Director of FHCRC and pioneered the use of genetics to define the cell cycle and to understand its control and role in carcinogenesis. He is a member of the National Academy of Sciences and has received numerous awards for his research, including the Albert Lasker Basic Medical Research Award. In 2001, Dr. Hartwell received the Nobel Prize in Physiology or Medicine for his work on the genetic control of cell division and the discovery of cell cycle checkpoints that signal arrest of the cell cycle in the presence of DNA damage. His current research focus is on the early detection of cancer.

Leroy HOOD, M.D., Ph.D. (Institute for Systems Biology) [lhood@systemsbiology.org]
Dr. Hool is recognized as one of the world's leading scientists in molecular biotechnology and genomics. Dr. Hood earned an M.D. from Johns Hopkins University in 1964 and a Ph.D. in biochemistry from the California Institute of Technology in 1968. Since then, his research has focused on the study of molecular immunology and biotechnology.

Gabriel HORTOBAGYI, M.D. (MD Anderson Cancer Center) [ghortoba@mdanderson.org]
Dr. Hortobagyi, Chair of Breast Medical Oncology and Director of the Breast Cancer Research Program at The University of Texas MD Anderson Cancer Center, will oversee the activities of the Consortium Specimen Resource. One of the world's leading authorities on the use of chemotherapy for treatment of breast cancer, Dr. Hortobagyi has been instrumental in developing combination chemotherapy for previously inoperable breast tumors and for improving multidisciplinary treatment for patients with all stages of breast cancer, including advanced disease. He is widely known for a landmark study he initiated in 1974 which showed that many large tumors could be reduced as much as 50 percent prior to surgery if patients were given neoadjuvant chemotherapy. Dr. Hortobagyi has published more than 600 articles and 100 book chapters. Dr. Hortobagyi currently holds the Nellie B. Connally Chair in Breast Cancer at MD Anderson and also chairs the Health Advisory Board of the Susan G. Komen Breast Cancer Foundation.

Peter W. LAIRD, Ph.D. (University of Southern California/Norris Cotton Cancer Center) [plaird@usc.edu]
Dr. Laird has extensive experience in the development of DNA methylation analysis technology. Dr. Laird earned his B.S. and M.S., cum laude, from the University of Leiden, Netherlands in 1982 and 1984, respectively. In 1997, he became Director of Research for the Department of Surgery at the University of Southern California. His work there has led to the invention of two new DNA methylation analysis techniques, COBRA, published in 1997, and MethyLight, published in 1999 and patented in 2001.

Eric LANDER, Ph.D. (The Broad Institute) [lander@broad.mit.edu]
Dr. Lander, a geneticist, molecular biologist, and mathematician, is founder and Director of the Whitehead Institute/MIT Center for Genome Research (WICGR), one of the world's leading genome centers, and Professor of Biology at MIT. Under Dr. Lander's leadership, WICGR has developed many of the key tools used in modern human and mammalian genomics and has applied them to pioneer new approaches to understanding the basis of disease. Dr. Lander was named a Rhodes Scholar in 1978 and received a MacArthur Foundation Fellowship in 1987 for his work in genetics. He was elected to the U.S. National Academy of Sciences in 1997, the U.S. Institute of Medicine in 1998, and the American Academy of Arts and Sciences in 1999. He has received numerous awards and honorary degrees and has served on many advisory boards for governments, academic institutions, scientific societies, and companies.

Martin MCINTOSH, Ph.D. (Fred Hutchinson Cancer Research Center) [mmcintos@fhcrc.org]
Dr. McIntosh is an Associate Member in the Public Health Sciences Division at the FHCRC and Head of the Center's Comparative Proteomics Computational Group. He is also an Associate Professor in the University of Washington Department of Biostatistics. He presently serves in leadership positions both at FHCRC and nationally, including on advisory panels for early detection (three NCI and one cancer institute). He is one of 35 founding members of the American HUPO Council, the North American arm of the worldwide HUPO initiative. Dr. McIntosh is PI of the early detection project of the FHCRC's ovarian cancer SPORE and Co-PI of a NCI-funded R01 for predicting cancer progression in cervical cancer. He is also Co-Investigator on three NCI and DOD-funded research projects for early detection biomarker discovery and evaluation. He has authored several publications on theoretical and practical considerations for combining biomarkers, algorithms for cancer early detection, screening algorithms and others. Dr. McIntosh will lead the Consortium's informatics development team at FHCRC, which will undertake development of the database and computational infrastructure.

Amanda PAULOVICH, M.D., Ph.D. (Fred Hutchinson Cancer Research Center) [apaulovi@fhcrc.org]
Dr. Paulovich is board-certified and fully licensed in Internal Medicine, board-eligible in Adult Oncology, and has three years of clinical experience diagnosing and treating malignancies. While a graduate student in Genetics, she trained in the laboratory of Dr. Lee Hartwell studying checkpoint regulation of cell cycle progression in yeast in response to DNA damaging agents. As a postdoctoral fellow with Eric Lander and Todd Golub at the Whitehead Institute Center for Genome Research, she gained considerable genomics experience designing and generating large microarray datasets, geared at finding biomarkers of cancer risk. In September 2003, she joined the faculty of the Clinical Research Division at Fred Hutchinson Cancer Research Center, where she is continuing to pursue her interest in biomarkers of cancer risk and detection.

Aysegul SAHIN, M.D. (MD Anderson Cancer Center) [asahin@mdanderson.org]
Dr. Sahin is Professor of Pathology and Director of the Breast Tumor Bank at MD Anderson Cancer Center. She received her M.D. from the University of Ankara School of Medicine in Ankara, Turkey, in 1980. She went on to complete a residency in Anatomic and Clinical Pathology at Oregon Health Sciences, a fellowship in Surgical Pathology at the University of Iowa Hospitals and Clinics, and a fellowship in Pathology at MD Anderson. She has been a faculty member in the Department of Pathology at MD Anderson since 1988. She was named Director of the Breast Tumor Bank in 1995, Co-Director of the Surgical Pathology Fellowship Program in 1998, Director of the Breast Pathology Fellowship Program in 2000, and Director of the Surgical Pathology Fellowship Program in 2001. During her time at MD Anderson, she has authored 140 articles published in peer-reviewed journals, 7 book chapters and teaching manuals, and numerous abstracts on topics such as histopathologic evaluation of prognostic and predictive markers of breast carcinogenesis, classification and the biologic behavior of premalignant lesions, evaluation of sentinel lymph nodes and biomarkers predicting neoadjuvant chemotherapy, and targeted therapies for breast cancer.

Nathalie SCHOLLER, M.D., Ph.D. (Fred Hutchinson Cancer Research Center) [nscholle@fhcrc.org]
Dr. Scholler is a Senior Staff Scientist in the Public Health Sciences Division of the FHCRC. Her primary research interests are investigating the immune response to cancer and developing diagnostic tests for cancer's early detection. Dr. Scholler received her M.D. from the Medical School of Marseille, France in 1988 and her Ph.D. in Immunology from the Center of Immunology of Marseille-Luminy (CIML) at the University of Aix-Marseille II, France, in 1995. Dr. Scholler is a member of the American Society of Gene Therapy, the American Association for the Advancement of Science, and the American Association of Immunologists.

Richard D. SMITH, Ph.D. (Battelle/Pacific Northwest National Laboratory) [dick.smith@pnl.gov]
Dr. Smith has extensive experience in proteomics, separations mass spectrometry, and the development of advanced methods and instrumentation. Dr. Smith received his Chemistry B.S. at Lowell Technological Institute and his Physical Chemistry Ph.D. at the University of Utah.

Nicole URBAN, Sc.D. (Fred Hutchinson Cancer Research Center) [nurban@fhcrc.org]
Dr. Urban is a Member of the Cancer Prevention Research Program of the Public Health Sciences Division at the FHCRC, where she is Head of the Gynecologic Cancer Research Program and Principal Investigator of a Specialized Program of Research Excellence (SPORE) in Ovarian Cancer. Dr. Urban studied Biostatistics and Health Services Administration at the Harvard School of Public Health and is Research Professor of Health Services in the School of Public Health at the University of Washington. For the past 10 years, Dr. Urban has studied ways to improve the use, performance and efficacy of tests for early detection of breast and ovarian cancer. She is particularly interested in the evaluation of markers detectable in serum for use in cancer screening.

Hui ZHANG, Ph.D. (Institute for Systems Biology) [hzhang@systemsbiology.org]
Dr. Zhang is a Senior Research Scientist at the Institute for Systems Biology. Dr. Zhang developed a method to isolate and identify glycosylated peptides/proteins using solid-phase extraction of glycopeptides (SPEG) and liquid chromatography mass spectrometry (LC-MS). She has applied the method to study cell surface proteins and proteins secreted into body fluids.