New biomarkers for cancer therapies derived from the research could usher in superior clinical laboratory diagnostics that identify a patientâs suitability for personalized drug therapies and treatments
Once approved for clinical use, not only would these biomarkers become targets for specific cancer therapies, they also would require development of new diagnostic tests that anatomic pathologists could use to determine whether a biomarker was present in a patient.
If yes, the drug can be administered. If no, the patient is not a candidate for that drug. Thus, this research may produce both diagnostic biomarkers and therapeutic targets.
Relevance of In-Depth Tumor Profiling to Support Clinical Decision-Making
In the Swiss âTumor Profilerâ (TuPro) project, the research team is examining the cellular composition and biology of tumors of 240 patients with melanoma, ovarian cancer, and acute myeloid leukemia. Recruitment for the study began in 2018. Today, the melanoma cohort is fully enrolled, and the ovarian cancer and acute myeloid leukemia cohorts are nearing complete enrollment.
âThe Tumor Profiler Study is an observational clinical study combining a prospective diagnostic approach to assess the relevance of in-depth tumor profiling to support clinical decision-making (âfast diagnostic loopâ) with an exploratory approach to improve the biological understanding of disease (âexploratory science loopâ),â the TuPro website states.
In their published paper, the Swiss researchers say these three cancers were selected for the study âbased on the potential clinical benefit and availability of sufficient tumor material for simultaneous analysis across all technologies.â
The TuPro Projectâs findings are available to doctors who analyze them at interdisciplinary tumor board meetings and generate treatment options, creating a âfast diagnostic loopâ with an estimated four-week turnaround time from surgery to tumor board. âThis approach has the potential to alter current diagnostics and paves the way for the translation of comprehensive molecular profiling into clinical decision-making,â the studyâs authors wrote in Cancer Cell.
Could Oncologists Be Making Better Precision Medicine Decisions?
In its writeup on the TuPro Projectâs research, Precision Oncology News concluded that the Swiss study âis rooted in the researchersâ notion that oncologists are not making the best personalized treatment decisions for patients by relying just on targeted DNA profiling using next-generation sequencing and digital pathology-based tests.
âThe researchers within the TuPro consortium hypothesized that integrating a more comprehensive suite of omics tests could lead to a more complete understanding of patientsâ tumors, including providing insights into the tumor microenvironment, heterogeneity, and ex vivo responses to certain drugs. This, in turn, could help inform the best course of treatment,â Precision Oncology News added.
âWith the Tumor Profiler study, we want to show that the widespread use of molecular biological methods in cancer medicine is not only feasible, but also has specific clinical benefits,â said TuPro consortium member Viola Heinzelmann-Schwarz, MD, Head of Gynecological Oncology at University Hospital Basel, in an ET Zurich news release.
New Precision Medicine Biomarkers from TuProâs Molecular Analysis
Researchers in the study also are investigating whether and what influence the molecular analysis had on doctorsâ therapy decisions.
The University Hospital Basal blog notes the long-term benefits of the Tumor Profiler approach is to expand the personalized-medicine therapy options for patients, including determining whether patients would benefit in certain cases âif they were not treated with drugs from standard therapy, but with drugs that have been approved for other types of cancer.â
Anatomic pathologists and clinical laboratory scientists will want to take note of the TuPro projectâs ultimate success or failure, since it could usher in changes in cancer treatments and bring about the need for new diagnostic tests for cancer biomarkers.
Experts list the top challenges facing widespread adoption of proteomics in the medical laboratory industry
Year-by-year, clinical
laboratories find new ways to use mass spectrometry to
analyze clinical specimens, producing results that may be more precise than
test results produced by other methodologies. This is particularly true in the
field of proteomics.
However, though mass spectrometry is highly accurate and
fast, taking only minutes to convert a specimen into a result, it is not fully
automated and requires skilled technologists to operate the instruments.
Thus, although the science of proteomics is advancing
quickly, the average pathology laboratory isnât likely to be using mass
spectrometry tools any time soon. Nevertheless, medical
laboratory scientists are keenly interested in adapting mass spectrometry
to medical lab test technology for a growing number of assays.
Molly Campbell, Science Writer and Editor in Genomics, Proteomics, Metabolomics, and Biopharma at Technology Networks, asked proteomics experts âwhat, in their opinion, are the greatest challenges currently existing in proteomics, and how can we look to overcome them?â Hereâs a synopsis of their answers:
Lack of High Throughput Impacts Commercialization
Proteomics isnât as efficient as it needs to be to be
adopted at the commercial level. Itâs not as efficient as its cousin genomics. For it to become
sufficiently efficient, manufacturers must be involved.
John Yates
III, PhD, Professor, Department of Molecular Medicine at Scripps Research California
campus, told Technology
Networks, âOne of the complaints from funding agencies is that you can
sequence literally thousands of genomes very quickly, but you canât do the same
in proteomics. Thereâs a push to try to increase the throughput of proteomics
so that we are more compatible with genomics.â
For that to happen, Yates says manufacturers need to
continue advancing the technology. Much of the research is happening at
universities and in the academic realm. But with commercialization comes
standardization and quality control.
âItâs always exciting when you go to ASMS [the conference for the American Society
for Mass Spectrometry] to see what instruments or technologies are going to be
introduced by manufacturers,â Yates said.
There are signs that commercialization isnât far off. SomaLogic, a privately-owned American protein
biomarker discovery and clinical diagnostics company located in Boulder, Colo.,
has reached the commercialization stage for a proteomics assay platform called SomaScan. âWeâll be
able to supplant, in some cases, expensive diagnostic modalities simply from a
blood test,â Roy
Smythe, MD, CEO of SomaLogic, told Techonomy.
Achieving the Necessary Technical Skillset
One of the main reasons mass spectrometry is not more widely
used is that it requires technical skill that not many professionals possess.
âFor a long time, MS-based proteomic analyses were technically demanding at
various levels, including sample processing, separation science, MS and the
analysis of the spectra with respect to sequence, abundance and
modification-states of peptides and proteins and false discovery rate
(FDR) considerations,â Ruedi
Aebersold, PhD, Professor of Systems Biology at the Institute of Molecular Systems Biology (IMSB) at
ETH Zurich, told Technology
Networks.
Aebersold goes on to say that he thinks this specific
challenge is nearing resolution. He says that, by removing the problem created
by the need for technical skill, those who study proteomics will be able to
âmore strongly focus on creating interesting new biological or clinical
research questions and experimental design.â
Yates agrees. In a paper titled, âRecent Technical Advances in
Proteomics,â published in F1000 Research, a peer-reviewed open research
publishing platform for scientists, scholars, and clinicians, he wrote, âMass
spectrometry is one of the key technologies of proteomics, and over the last
decade important technical advances in mass spectrometry have driven an
increased capability of proteomic discovery. In addition, new methods to
capture important biological information have been developed to take advantage
of improving proteomic tools.â
No High-Profile Projects to Stimulate Interest
Genomics had the Human Genome Project
(HGP), which sparked public interest and attracted significant funding. One of
the big challenges facing proteomics is that there are no similarly big,
imagination-stimulating projects. The work is important and will result in
advances that will be well-received, however, the field itself is complex and difficult
to explain.
Emanuel
Petricoin, PhD, is a professor and co-director of the Center for Applied
Proteomics and Molecular Medicine at George
Mason University. He told Technology
Networks, âthe field itself hasnât yet identified or grabbed onto a
specific âmoon-shotâ project. For example, there will be no equivalent to the
human genome project, the proteomics field just doesnât have that.â
He added, âThe equipment needs to be in the background and
what you are doing with it needs to be in the foreground, as is what happened
in the genomics space. If itâs just about the machinery, then proteomics will
always be a âpoor step-childâ to genomics.â
Democratizing Proteomics
Alexander
Makarov, PhD, is Director of Research in Life Sciences Mass Spectrometry
(MS) at Thermo Fisher
Scientific. He told Technology
Networks that as mass spectrometry grew into the industry we have today,
âeach new development required larger and larger research and development teams
to match the increasing complexity of instruments and the skyrocketing
importance of software at all levels, from firmware to application. All this
extends the cycle time of each innovation and also forces [researchers] to
concentrate on solutions that address the most pressing needs of the scientific
community.â
Makarov describes this change as âthe increasing democratization of MS,â and says that it âbrings with it new requirements for instruments, such as far greater robustness and ease-of-use, which need to be balanced against some aspects of performance.â
One example of the increasing democratization of MS may be
several public proteomic datasets available to scientists. In European
Pharmaceutical Review, Juan
Antonio ViscaĂno, PhD, Proteomics Team Leader at the European Bioinformatics Institute (EMBL-EBI)
wrote, âThese datasets are increasingly reused for multiple applications, which
contribute to improving our understanding of cell biology through proteomics
data.â
Sparse Data and Difficulty Measuring It
Evangelia
Petsalaki, PhD, Group Leader EMBL-EBI, told Technology
Networks there are two related challenges in handling proteomic data.
First, the data is âvery sparseâ and second â[researchers] have trouble
measuring low abundance proteins.â
Petsalaki notes, âevery time we take a measurement, we
sample different parts of the proteome or phosphoproteome and
we are usually missing low abundance players that are often the most important
ones, such as transcription
factors.â She added that in her group they take steps to mitigate those
problems.
âHowever, with the advances in MS technologies developed by
many companies and groups around the world ⊠and other emerging technologies
that promise to allow âsequencingâ proteomes, analogous to genomes ⊠I expect
that these will not be issues for very long.â
So, what does all this mean for clinical laboratories? At the
current pace of development, its likely assays based on proteomics could become
more common in the near future. And, if throughput and commercialization ever
match that of genomics, mass spectrometry and other proteomics tools could
become a standard technology for pathology laboratories.
At least thatâs what researchers at ETH Zurich (ETH), an international university for technology and natural sciences, have concluded. They published the results of their study in Cell.
âHere, we present a chemoproteomic workflow for the systematic identification of metabolite-protein interactions directly in their native environments,â the researchers wrote. âOur data reveal functional and structural principles of chemical communication, shed light on the prevalence and mechanisms of enzyme promiscuity, and enable extraction of quantitative parameters of metabolite binding on a proteome-wide scale.â
Interactomics address interactions between proteins and small molecules, according to an article published in Technology Networks. The terms âinteractomicsâ and âomicsâ were inspired by research that described, for the first time, the interactions and relationships of all proteins and metabolites (A.K.A, small molecules) in the whole proteome.
Medical laboratories and anatomic pathologists have long understood the interactions among proteins, or between proteins and DNA or RNA. However, metabolite interactions with packages of proteins are not as well known.
These new omics could eventually be an important source of diagnostic biomarkers. They may, one day, contribute to lower cost clinical laboratory testing for some diseases, as well.
Metabolite-Protein Interactions are Key to Cellular Processes
The ETH researchers were motivated to explore the interplay between small molecules and proteins because they have important responsibilities in the body. These cellular processes include:
âMetabolite-protein interactions control a variety of cellular processes, thereby playing a major role in maintaining cellular homeostasis. Metabolites comprise the largest fraction of molecules in cells. But our knowledge of the metabolite-protein interaction lags behind our understanding of protein-protein or protein-DNA interactomes,â the researchers wrote in Cell.
Leveraging Limited Proteolysis and Mass Spectrometry
The researchers used limited proteolysis (LiP) technology with mass spectrometry to discover metabolite-protein interactions. Results aside, experts pointed out that the LiP technology itself is significant.
âIt is one of the few methods that enables the unbiased and proteome-wide profiling of protein conformational changes resulting from interaction of proteins with compounds,â stated a Biognosys blog post.
Biognosys, a proteomics company founded in 2008, was originally part of a lab at ETH Zurich.
The ETH team focused on the E. coli bacterial cell in particular and how its proteins and enzymes interact with metabolites.
âAlthough the metabolism of E. coli and associated molecules is already very well known, we succeeded in discovering many new interactions and the corresponding binding sites,â Paola Picotti, PhD, Professor of Molecular Systems Biology at ETH Zurich, who led the research, told Technology Networks. âThe data that we produce with this technique will help to identify new regulatory mechanisms, unknown enzymes and new metabolic reactions in the cell,â she concluded. (Photo copyright: ETH Zurich.)
More than 1,000 New Interactions Discovered
The study progressed as follows, according to Technology Networksâ report:
âCellular fluid, containing proteins, was extracted from bacterial cells;
âStrikingly, more than 80% of the reported interactions were novel and about one quarter of the measured proteome interacted with at least one of the 20 tested metabolites. This indicates that the metabolite-protein interaction network is vast and largely uncharted,â Papp stated in an ETH Zurich Faculty of 1000 online article.
According to Technology Networks, âPicotti has already patented the method. The ETH spin-off Biognosys is the exclusive license holder and is now using the method to test various drugs on behalf of pharmaceutical companies.â
The pharmaceutical industry is reportedly interested in the approach as a way to ascertain drug interactions with cellular proteins and their effectiveness in patient care.
The ETH Zurich study is compelling, especially as personalized medicine takes hold and more medical laboratories and anatomic pathology groups add molecular diagnostics to their capabilities.
Researchers believe they have begun to crack open a âblack boxâ involving the genomes and diseases of individual patients
Researchers in Switzerland are developing a new way to use mass spectrometry to explain why patients respond differently to specific therapies. The method potentially could become a useful tool for clinical laboratories that want to support the practice of precision medicine.
It is also one more example of how mass spectrometry is being used by researchers to develop new types of diagnostic assays that perform as well as traditional clinical laboratory testing methods, such as chemistry and immunoassay.
Thus, the latest research from the Swiss Federal Institute of Technology in Lausanne (EPFL) and ETH Zurich (ETHZ), will be of interest to pathology laboratory managers and medical laboratory scientists. It combines SWATH-MS (Sequential Window Acquisition of all Theoretical Mass Spectra) with genomics, transcriptomics, and other âomics,â to explain why patients respond differently to specific therapies, and to formulate a personalized strategy for individual treatment. (more…)
Prototype could provide glimpse of radically different future for patient monitoring and present new opportunities for pathologists and medical laboratory scientists
Are pathologists and medical laboratory scientists ready for a new diagnostic paradigm? Instead of specimens transported into a central medical laboratory, how about in vivo real-time monitoring of patients with chronic diseases, where pathologists are able to remotely spot changes in a patientâs condition as they happen and alert physicians to take timely action?
Researchers are combining several technologies to create sensor-based systems for in vivo real-time monitoring of body processes. In Basel, Switzerland, a team at ETH Zurichâs Department of Biosystems Science and Engineering created an implantable sensor for continuous monitoring of blood pH that is paired up with a gene feedback mechanism to produce the necessary amount of insulin. The dual function device has been described as a âmolecular prosthesis.â The purpose of this device is to monitor patients with diabetes.
While ETH Zurichâs prototype needs more development before it will be ready for clinical uses, the universityâs research shows pathologists and medical laboratory scientists how fast new capabilities are being developed that can eventually support a radically different approach to patient diagnosis and patient monitoring. Use of such real-time in vivo diagnostic devices could allow laboratory professionals to remotely monitor patients and trigger clinical interventions when the biomarkers being tracked indicate such a need.
Device Monitors Blood Acidity: Responds to Diabetic Acidosis by Producing Insulin
What is particularly intriguing about the device created by the Swiss universityâs bioengineers is that it is capable of both diagnostic and therapeutic actions. Both modules of the deviceâthe blood pH sensor and insulin production mechanismâare constructed from biological components, such as various genes and proteins. These are incorporated into cultivated renal cells. The researchers then embedded millions of these customized cells in capsules that can be used as implants in the body.
According to an ETH news release, the pH sensor transmits a signal to trigger the production of insulin if pH values fall below 7.35, a low pH value specific for type 1 diabetes. Once blood pH returns to the ideal range, the sensor turns itself off and the reprogrammed cells stop producing insulin.
In tests using mice with type 1 diabetes, the ETH device was able to successfully monitor the bloodâs acidity and respond to diabetic acidosis by producing insulin. Mice with capsules implanted produced the amount of insulin appropriate to their individual acid measurements, enabling them to have hormone levels comparable to that of healthy mice. The implant also compensated for larger deviations in blood sugar. The system design and test results were published in an August 7, 2014, Molecular Cell article.
ETH Prototype Shows the Possibility of Creating Applications for Humans
Despite the promising results, Martin Fussenegger, Ph.D., Professor in ETH Zurichâs Department of Biosystems Science and Engineering, says the university will need an industrial partner in order to consider commercial development of the molecular device.
âApplications for humans are conceivable based on this prototype, but they are yet to be developed,â stated Fussenegger in the news release. âWe wanted to create a prototype first to see whether molecular prostheses could even be used for such fine adjustments to metabolic processes.â
Martin Fussenegger, Ph.D., Professor in ETH Zurichâs Department of Biosystems Science and Engineering, says the initial results of studies in mice of ETH Zurichâs implantable molecular device for regulating blood pH levels through a closed loop pH sensing and insulin production mechanism shows promise. (Photo copyright ETH Zurich)
Until recently, most progress in diabetes care focused on improvements to continuous glucose monitors and insulin delivery systems, with implantable, long-lasting sensors for continuous monitoring on the horizon. ETH Zurichâs implantable molecular device would represent a major leap forward.
Diabetes in U.S. Continues to Increase
A 2014 report from the U.S. Centers for Disease Control and Prevention (CDC) shows that diabetes is on the rise, with 29.1 million people (9.3% of the U.S. population) living with diabetes. By comparison, in 2010 there were an estimated 26 million people in the U.S. with diabetes.
The CDC says that nearly 28% of people with diabetes are undiagnosed, which increases risk for heart disease, stroke, blindness, kidney failure, amputation of toes, feet or legs, and early death.
The report also estimates that the total cost in medical bills and lost work and wages due to diabetes and related complications adds up to $245 billion, up from $174 billion in 2010.
âThese new numbers are alarming and underscore the need for an increased focus on reducing the burden of diabetes in our country,â said Ann Albright, Ph.D., R.D., Director of the CDCâs Division of Diabetes Translation, in a CDC news release. âDiabetes is costly in both human and economic terms. Itâs urgent that we take swift action to effectively treat and prevent this serious disease.â
Ann Albright, Ph.D., R.D., Director of the Centers for Disease Control and Preventionâs Division of Diabetes Translation, stresses the importance of continued diabetes research. (Photo copyright CDC)
The need for new methods to control diabetes was underscored in a 2010 study published at PubMed Central (PMC) on the U.S. National Institutes of Healthâs National Library of Medicine (NIH/NLM) website. It painted a âsobering picture of the future growth of diabetes.â
âUnder an assumption of low incidence and relatively high diabetes mortality, total prevalence is projected to increase to 21% of the U.S. adult population by 2050,â the authors wrote. âOn the other hand, if recent increases in diabetes incidence continue (middle incidence projections) and diabetes mortality ratios are relatively low, diabetes prevalence will increase to 33% by 2050.â
The study blames the rise in diabetes in the U.S. in part on demographic changes brought about by an aging populationâolder adults are more likely to develop diabetesâan increase in minority populations that report higher diabetes rates, and reduced mortality rates for those living with the disease.
In Vivo and In Vitro Diagnostics Continue to Merge
Dark Daily has reported on the evolution of implantable diagnostic tests for some time. As we noted in âIn Vivo Pathology Testing Might Use Injectable Microbeads to Detect Excessive Glucose Levelsâ (Dark Daily, January 1, 2011), pathology researchers continue to find novel ways to integrate in vivo and in vitro diagnostic tests. This trend does not appear to be slowing.
Implantable diagnostic technology continues to develop, which should indicate to clinical laboratories the possibility that disease diagnosis and monitoring is shifting away from centralized laboratories and towards medical communities and patientsâ homes. The added twist in the new in vivo device created by researchers at ETH Zurich is that, after the diagnostic component of the device has tracked a change in the biomarker, the device can then automatically produce the appropriate therapy, also in real time and in vivo.