Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Study of biomarker development in mice provides a roadmap for a similar approach in humans

20.06.2011
Researchers at Fred Hutchinson Cancer Research Center have demonstrated in mice that the performance of a novel biomarker-development pipeline using targeted mass spectrometry is robust enough to support the use of an analogous approach in humans. The findings, by principal investigator Amanda Paulovich, M.D., Ph.D., an associate member of the Hutchinson Center's Clinical Research Division, are published in Nature Biotechnology.

Paulovich and colleagues demonstrated that a staged, targeted pipeline approach using mass spectrometry to prioritize and validate proteins of interest enabled them to test a far larger number of biomarker candidates than would have been possible using conventional technologies, making a substantial improvement over the current state of biomarker evaluation.

"If, as we hope, this approach enables more efficient translation of novel biomarkers into use as diagnostic tests, the effect will be an improved ability to personalize medicine by optimizing our treatment of individual patients, thus improving patient outcomes and also helping to contain health care costs," Paulovich said.

The researchers undertook this proof-of-concept study in an attempt to accelerate and streamline the process of biomarker candidate testing because, over nearly a decade, hundreds of millions of dollars have been spent on the discovery of promising protein biomarkers of human diseases, particularly biomarkers found in the blood. Despite this significant investment, the number of new FDA-approved blood-based biomarkers has remained very low.

Several factors have contributed to this low return on investment. Each promising biomarker must be further studied in clinical trials, which requires researchers to measure the abundance of each candidate biomarker in hundreds of patient samples. Because the odds are extraordinarily low that any one biomarker candidate will provide clinically useful information, large numbers of candidates must be tested if there is to be any hope of identifying a clinically useful biomarker.

"Unfortunately, there is a major bottleneck in the biomarker-development pipeline because there are no quantitative tests for the majority of human proteins," Paulovich said. "As a result, tests must be developed from scratch for clinical analysis of candidate biomarkers, and this process is prohibitively expensive for testing large numbers of candidate proteins. As a result, few promising biomarkers undergo rigorous validation, and the literature is replete with lists of candidates that have not been thoroughly tested."

For the project, Paulovich and colleagues used a highly sensitive and targeted analytical technology – selected reaction monitoring mass spectrometry. This type of mass spectrometry is not new – it has been used for years in clinical laboratories worldwide to measure drug metabolites and small molecules associated with inborn errors of metabolism. What is new is their pioneering use of this technology in a pipeline to test candidate protein biomarkers. Unlike traditional mass spectrometry, which attempts to detect all proteins in a biological sample in a scattershot fashion, this technology is highly targeted, allowing researchers to calibrate the equipment to specifically look for peptides, or protein fragments, of interest, filtering out the rest as white noise.

Targeted mass spectrometry methods, particularly when combined with antibody-based enrichment of target proteins, provide a technology platform for highly specific, reproducible and sensitive quantification of many proteins from a small drop of blood. Mass spectrometry-based tests have several advantages over traditional technologies, and they can be performed more quickly and at a lower cost.

"We aimed to test the possibility that a staged biomarker pipeline based on targeted mass spectrometry would enable the prioritization and testing of very large numbers of candidate biomarkers in preclinical trials. The hope was that this would enable more comprehensive testing of candidate biomarkers and thus a greater success rate for clinical validation."

Stage one of the biomarker discovery pipeline involved using targeted mass spectrometry to detect candidate biomarker proteins in the blood. Stage two sought to determine whether these proteins were elevated in the blood of mice with breast cancer as compared to healthy mice. Stage three involved developing blood tests that could be used in preclinical trials to detect the most promising protein candidates associated with early breast cancer development.

Although previous work, including that of Paulovich and colleagues, had analyzed the performance of the individual stages in isolation, these components had never before been assembled into a pipeline, and the numbers of proteins tested in previous studies were generally too small to demonstrate the feasibility of translating to clinical use.

For the study, the researchers tested 80 blood samples from healthy control mice and mice harboring preclinical or clinically apparent breast cancers. They also studied a group of mice that experience conditions that commonly affect the results of cancer screening tests. The researchers found 36 blood biomarkers of breast cancer in this mouse model. Of these, two were elevated in the blood of tumor-bearing mice before the tumors could be seen or felt, indicating that they enabled early detection of the cancers.

The purpose of the study was not to find biomarkers for breast cancer that would be of use in humans, but rather to develop and test technologies in a preclinical model before embarking on human studies. "It remains to be tested whether any of the specific biomarkers identified in the mouse will be of use in humans, where disease and biological variation will be much greater than in a mouse model. It is more likely that we have developed a road map for conducting more effective biomarker studies in humans," Paulovich said.

Other Hutchinson Center collaborators on the study included Peter Nelson, M.D., and Christopher Kemp, Ph.D., of the Human Biology Division; Martin McIntosh, Ph.D., and Pei Wang, Ph.D., of the Public Health Sciences Division; and Phil Gafken, director of the Center's Proteomics Laboratory.

The study was made possible with funding from the Paul G. Allen Family Foundation and from the Clinical Proteomic Technology Assessment for Cancer (CPTAC) program of the National Cancer Institute.

At Fred Hutchinson Cancer Research Center, our interdisciplinary teams of world-renowned scientists and humanitarians work together to prevent, diagnose and treat cancer, HIV/AIDS and other diseases. Our researchers, including three Nobel laureates, bring a relentless pursuit and passion for health, knowledge and hope to their work and to the world. For more information, please visit fhcrc.org.

Kristen Woodward | EurekAlert!
Further information:
http://www.fhcrc.org

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>