New Biomarker Method Could Increase the
Number of Diagnostic Tests for Cancer
A team of researchers has demonstrated that a new method for detecting
and quantifying protein biomarkers in body fluids may ultimately
make it possible to screen multiple biomarkers in hundreds of patient
samples, thus ensuring that only the strongest biomarker candidates
will advance down the development pipeline. The researchers have
developed a method with the potential to increase accuracy in detecting
real cancer biomarkers that is highly reproducible across laboratories
and a variety of instruments so that cancer can be caught in its
The results of the Clinical Proteomic Technology Assessment for
Cancer (CPTAC) study, which is sponsored by the National Cancer
Institute (NCI), part of the National Institutes of Health, and
partner organizations, appeared online June 28, 2009, in Nature
"These findings are significant because they provide a potential
solution for eliminating one of the major hurdles in validating
protein biomarkers for clinical use. Thousands of cancer biomarkers
are discovered every day, but only a handful ever makes it through
clinical validation. This is a critical roadblock because biomarkers
have the potential to allow doctors to detect cancer in the earliest
stages, when treatment provides the greatest chances of survival," said
John E. Niederhuber, M.D., NCI director. "The critical limiting
factor to date in validating biomarkers for clinical use has been
the lack of standardized technologies and methodologies in the
biomarker discovery and validation process, and this research may
solve that dilemma."
The collaborative and multi-institute nature of this work was
critical because many other technologies have yielded test results
that vary greatly from one laboratory to the next. NCI’s Clinical
Proteomic Technologies for Cancer (CPTC) program was established
to help solve this problem. The five institutes that participated
in this research as part of the NCI-sponsored CPTAC include the
Broad Institute of the Massachusetts Institute of Technology and
Harvard, Cambridge, Mass.; Vanderbilt-Ingram Cancer Center, Nashville,
Tenn.; University of California, San Francisco; Purdue University,
West Lafayette, Ind., and Memorial Sloan-Kettering Cancer Center,
New York City.
Proteomics studies interactions between proteins, which often
work in a tag-team fashion to send important signals within a cell.
Most proteomic technologies have been based on mass spectrometry,
a decades-old technology that determines which proteins are in
a specimen based on the mass and electric charge of fragments of
The current biomarker discovery process typically identifies hundreds
of candidate biomarkers in each study using small numbers of samples,
leading to very high rate of invalid biomarkers. The biomarkers
that are actually valid — that is, true biomarkers — must
be culled from lengthy lists of candidates, a time-consuming and
not always accurate process.
The CPTAC center network study demonstrates that new applications
of existing proteomic techniques show promise of greater accuracy.
The findings suggest that two technologies — multiple reaction
monitoring (MRM) coupled with stable isotope dilution mass spectrometry
(SID-MS), which is a technique used by protein scientists to measure
the abundance of a particular protein in a sample — may be
suitable for use in preclinical studies to rapidly screen large numbers
of candidate protein biomarkers in the hundreds of patient samples
necessary for verification.
MRM provides a rapid way to determine whether a candidate biomarker
is detectable in blood. This is critically important for clinical
use, as well as in being able to assess whether changes in a candidate
biomarker correspond with the presence or stage of a disease. A
sophisticated type of mass spectrometry, MRM is designed for obtaining
the maximum sensitivity for quantifying target compounds in patient
"Our work demonstrates that this technology has the potential
to transform how candidate protein biomarkers are evaluated. SID-MRM-MS,
combined with complementary techniques, could provide the critical
filter to assess protein candidate performance without the immediate
need for other detection or quantification tests. This would provide
the critical missing component for a systematic biomarker pipeline
that bridges discovery and clinical validation," said senior
author Steven Carr, Ph.D., director of the Proteomics Platform
at the Broad Institute. "This is an important step forward
for the field of proteomics, one that would not have been possible
without the collaborative efforts of the CPTAC partners."
In this study, the researchers demonstrated that MRM is highly
sensitive and specific, important characteristics that ensure the
detection of real disease-specific biomarkers. In addition, using
common samples and standardized protocols, they found that MRM
is highly reproducible across laboratories and technology platforms.
Clinical Proteomic Technologies for Cancer will make common samples
and standardized protocols available through its reagents data
portal, which can be accessed at http://proteomics.cancer.gov.
This new work grew from a memorandum of understanding between
the NCI (through Clinical Proteomic Technologies for Cancer) and
the U.S. Food and Drug Administration to accelerate proteomics
technology development and application in clinical settings.
CPTAC’s goal is to empower the research community with the tools
and methods needed to translate proteomics from laboratory research
to clinical utility. These efforts should have implications far
beyond cancer, ultimately affecting the diagnosis and treatment
of much human disease.
The full listing of participating institutes includes the Broad
Institute of the Massachusetts Institute of Technology and Harvard
(with the Fred Hutchinson Cancer Research Center, Massachusetts
General Hospital, the University of North Carolina at Chapel Hill,
the University of Victoria and the Plasma Proteome Institute),
Memorial Sloan-Kettering Cancer Center (with the Skirball Institute
at New York University), Purdue University (with Monarch Life Sciences,
Indiana University, Indiana University-Purdue University Indianapolis
and the Hoosier Oncology Group ), University of California, San
Francisco (with the Buck Institute for Age Research, Lawrence Berkeley
National Laboratory, the University of British Columbia and the
University of Texas M.D. Anderson Cancer Center), and Vanderbilt
University School of Medicine (with the University of Texas M.D.
Anderson Cancer Center, the University of Washington and the University
The Eli and Edythe L. Broad Institute of MIT and Harvard was founded
in 2003 to empower this generation of creative scientists to transform
medicine with new genome-based knowledge. The Broad Institute seeks
to define all the molecular components of life and their connections;
discover the molecular basis of major human diseases; develop effective
new approaches to diagnostics and therapeutics; and disseminate
discoveries, tools, methods and data openly to the entire scientific
community. Founded by MIT, Harvard and its affiliated hospitals,
and the visionary Los Angeles philanthropists Eli and Edythe L.
Broad, the Broad Institute includes faculty, professional staff
and students from throughout the MIT and Harvard biomedical research
communities and beyond, with collaborations spanning over a hundred
private and public institutions in more than 40 countries worldwide.
For further information about the Broad Institute, go to www.broad.mit.edu.
Memorial Sloan-Kettering Cancer Center is the world’s oldest and
largest private institution devoted to prevention, patient care,
research, and education in cancer. Their scientists and clinicians
generate innovative approaches to better understand, diagnose,
and treat cancer. Their specialists are leaders in biomedical research
and in translating the latest research to advance the standard
of cancer care worldwide. For more information, go to www.mskcc.org.
The Purdue University-Indiana University Analytical Proteomics
Team pairs Purdue's experts in mass spectrometry and proteomics
technology with the expert clinical team of cancer researchers
from Indiana University School of Medicine. The team works to assess
proteomic technology and its applications for the diagnosis and
treatment of cancer with a focus on technology to diagnose breast
and prostate cancer through blood samples. The team is based at
Purdue's Bindley Bioscience Center at Discovery Park.
UCSF is a leading university dedicated to promoting health worldwide
through advanced biomedical research, graduate-level education
in the life sciences and health professions, and excellence in
NCI leads the National Cancer Program and the NIH effort to dramatically
reduce the burden of cancer and improve the lives of cancer patients
and their families, through research into prevention and cancer
biology, the development of new interventions, and the training
and mentoring of new researchers. For more information about cancer,
please visit the NCI Web site at http://www.cancer.gov or call
NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
It is the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare diseases.
For more information about NIH and its programs, visit www.nih.gov.
Reference: Addona T, Abbatiello SE, et al. A multi-site
assessment of precision and reproducibility of multiple reaction
monitoring-based measurements by the NCI-CPTAC Network: toward quantitative
protein biomarker verification in human plasma. Online June 28, 2009,