Mass Spec Opens New Diagnostic Areas

October 10, 2017
Mass Spec Opens New Diagnostic Areas
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According to Jose Castro-Perez, Ph.D., director of global markets, Health Sciences with Waters, mass spectrometry today is an underused technology in the clinical lab. But it is one that can play a significant role to help guide early treatment and preventative care, especially diseases that are significantly caused, or influenced, by an individual’s lifestyle.

“Labs around the world are now embracing this technology to help them discover new biomarkers that can be converted to clinically actionable assays that can deliver benefit to patients,” Castro-Perez said.

Two examples of this are type 2 diabetes and cardiovascular disease. For type 2 diabetes diagnosis today, many patients will have their doctors take a glucose tolerance test. But using mass spectrometry as a tool may be more effective for predicting patients with a propensity for developing the disease.

“The doctor takes a blood sample, and (using mass spectrometry) measures a panel of metabolites that are indicative of insulin resistance,” he said. “You get a more preventative measurement. If you can do that, you can save billions of dollars in healthcare, because some of these diseases are preventable, especially cardiovascular disease. A lot of these diseases are affected by lifestyle and lack of exercise. This where I see the implementation of this technology can really take a huge leap forward, because the economics behind it makes a lot of sense.”

The potential for mass spectrometry to play a prognostic and diagnostic role in care is also continuing to evolve. Amrita Cheema, Ph.D., who is a professor in the department of oncology at Georgetown University School of Medicine, is using mass spectrometry to identify biomarkers that are predictive of the accidental or intentional exposure to radiation, and also biomarkers for the early detection of pancreatic cancer.

Currently the lab where Dr. Cheema works has National Cancer Institute funding to discover biomarkers predictive of patient outcomes who undergo radiation therapy. “The idea is to develop a diagnostic kit that will be available in a high-throughput format, to run in a clinical mass spec lab,” she said. “So the doctors can have the information on whether the patient will benefit from the therapy or not.”

While mass spectrometry-based tests for proteins and metabolites are slowly making their way into the clinical diagnostic arsenal, it some cases it is unlikely they will completely supplant some established testing methods, such as immunohistochemistry. However, there may be a role for MS-based tests in cases where IHC can’t accurately diagnose all patients.

One such area where mass spec plays a role is in monitoring thyroid cancer patients for the presence of thyroglobulin. Typcially, doctors will order an IHC thyroglobulin test for patients who have been treated for thyroid cancer to make sure the treatment was successful. No thyroglobulin present indicates the patient is cancer free.

Unfortunately, IHC accurately measures thyroglobulin in only 90% of patients. The other 10% percent of the population have anti-thyroglobulin autoantibodies circulating in their bodies which interfere with the IHC test.

“This is where mass spectrometry could be used for thyroglobulin,” said Dr. Kulasignam. “You’d find a proteotypic peptide, develop an SRM assay, and then just go after it because you won’t have the interference of this other molecule. That is what some groups have developed and are offering it routinely in the clinical diagnostic lab.”

Mass Spec Coming on Strong for Biomarker Identification, Diagnostic Tool

While mass spectrometry adoption may still be relatively low, it is poised to make a significant impact in the coming years in the clinical diagnostic lab. “There is currently a great opportunity in that space because that is an end goal, so the patient can benefit from diagnostic assays that are not achievable by other means,” said Dr. Castro-Perez.

As Dr. Castro-Perez sees it, the development of targeted panels for diagnostics and the fundamental research into the discovery of validated biomarkers will go hand in hand. “It will progress on both paths,” he said, “and will require the development of instrumentation that is fit for purpose for the biomarker discovery function, along with ready-to-use assays that have specific pathways, which clinicians will be interested in.”

But in the case of proteomics and metabolomics, the potential number of biomarkers to query makes this seems a daunting task. According to Dr. Castro a key trend moving researchers away from a shotgun approach to biomarker research are what he believes are requests to researchers and principal investigators coming from clinicians.

“More than ever there is interest from clinicians,” he concluded. “In the past it was a shotgun approach—let’s see if we can find an interesting signature and go from there. That was the old days. But clinicians think very differently. They are very issue driven and they understand numbers. They relate to an underlying phenotype or biology question. That is why I think the trend is changing.”

Dr. Cheema agrees, and thinks leveraging MS technologies via a top-down approach to proteomic research will help drive translation of new findings into the clinic. “Listening to people from the clinic, and understanding what their challenges are and what they would like allows researchers to design approaches for questions that are yet unanswered in areas of need,” she said.

While focusing on one or two biomarkers to provide clinically relevant information is one pathway that will help boost development and adoption of mass spec in the diagnostic lab, Vathany Kulasingam, Ph.D., a clinical biochemist at University Health Network, Toronto, whose work focuses on identifying protein biomarkers in ovarian cancer,thinks the future also hold spotential for broader assays.

“The future, I think, is in using proteomics and mass spectrometry for global profiling in the clinical diagnostics lab. We already have one such assay that looks at the biopsy tissue of individuals that have a disease called amyloidosis. If you take the tissue, digest it, and do a full proteome analysis you can subtype that disease and make a diagnosis,” she noted. “There will be many more opportunities to have global proteome profiling, whether from biopsy tissues or other biological samples.”