A Growing Interest in Biomarkers

The CIMIT Forum on Jan. 22 at Simches Research Center at Massachusetts General Hospital, addressed the topic, “Biomarkers: Cutting Edge Indicators to Assess Health, Monitor Disease or Determine Responsiveness to Therapy.”

Homer Pien, PhD, managing director, Center for Biomarkers in Imaging, at Massachusetts General Hospital, focused on the subject, “Imaging Biomarkers: Uses, Misuses, Successes and Failures.”

There is growing evidence that human medical imaging can help answer questions as they arise during the drug development process. Imaging modalities such as magnetic resonance imaging, computer tomography and positron emission tomography can offer insights into the bioactivity, pharmacokinetics and dosing of drugs.

Dr. Pien said that biomarkers could be an asset in the drug development process, which is both costly and risky.  He said that with recent advances in genomic, proteomic, imaging and computational sciences, the time is right for pharmaco-imaging to become an important tool in drug development.

He and his team of researchers encourage the broader academic, clinical, industrial and government communities to join forces and explore the potential for using imaging to improve translational research and to significantly reduce the time and costs of developing new pharmaceuticals.

Dr. Robert Gerszten, MD, is principal investigator, Massachusetts General Hospital Center for Immunology and Inflammatory Diseases, and MGH Cardiovascular Research Center; he is Senior Associate Member, Broad Institute; and he is  associate professor at Harvard Medical School. He spoke on “Metabolomic Approaches for Cardiovascular Biomarker Discovery.”

While decades of research in biochemistry, nutrition and physiology have revealed specific metabolic pathways, systemic surveys of pathways altered in human disease states such as atherosclerotic vascular disease are now possible. An emerging set of technologies, based on mass spectrometry, enables “metabolomics,” the monitoring of hundreds of metabolites from three biological samples.

These technologies promise to transform medicine’s ability to profile samples with the goal of illuminating biology and discovering valuable clinical biomarkets. Dr. Gerszten discussed the development of a targeted mass spectrometry-based metabolomics platform, and its application to perturbation studies in humans.

A. Gregory Sorensen, MD, director, Center for Biomarkers in Imaging, and associate director, Martinos Center for Biomedical Imaging, MGH; and associate professor of radiology at Harvard Medical School, moderated the session.

     

Imaging Biomarkers: Uses, Misuses, Successes, and Failures

In the mid-1980s two new drugs, flecainide and encainide, were introduced to reduce ventricular arrhythmias in asymptomatic patients with histories of heart disease.  The drugs did indeed reduce arrhythmias.  A large trial was undertaken to test the efficacy of the drugs, but the trial was stopped after a year because patients taking the drugs were found to be almost two-and-half times more likely to die than patients taking placebos.  Flecainide and encainide were recalled in 1991.  Their example demonstrates that improving a biomarker does not necessarily translate into increased survival. 

When assessing clinical outcomes, one should think very carefully before using a biomarker as a surrogate endpoint.  Biomarkers can be difficult to validate and require different levels of validation depending on their intended use.  A good biomarker should accurately reflect a direct effect of an intervention.    

Many new biomarkers are being developed that involve imaging technology.  Noninvasive cardiac imaging techniques, for example, are highly desirable and are actively being sought.  Cardiac computed tomography (CT) has great potential in this area, but its usefulness is currently limited by the fact that calcium deposits in imaged tissue decrease the technique’s sensitivity and specificity.  To address this problem, researchers funded by CIMIT have developed an iterative image reconstruction algorithm that is able to successfully eliminate some of the “calcium blooming” that has hampered the use of cardiac CT in the past. 

Another new imaging biomarker uses positron emission tomography (PET) to measure local uptake of radiolabeled glucose.  By tracking glucose, doctors can find sites of inflammation, such as stenotic arteries, because macrophages there take up glucose at high levels.  Tumors also take up a lot of glucose, so the imaging strategy can be used to monitor them as well.  Tracking radiolabeled glucose is a promising technique because it directly measures a step known to be crucial to inflammation and tumor growth. 

Imaging biomarkers have many advantages.  They are usually noninvasive, and they produce intuitive, multidimensional results.  They yield both qualitative and quantitative data and are relatively comfortable for patients.  To get as many benefits as possible from imaging techniques, the data produced should be combined with information from other sources.  Biomarkers will undoubtedly be useful in many ways, but clinicians and researchers should resist the temptation to jump on the buzzword “bandwagon” and should concentrate on the science behind the techniques.           

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