In recent years, tremendous strides have been made in the diagnosis and treatment of cancer, yet several sobering facts remain. Despite the knowledge we have gained, we still don't know which cancer patients will respond positively to chemotherapy treatment, or which patients will have a toxic reaction to the treatment.
Why do some treatments prove effective for some patients, but have no meaningful positive impact on others? Why do some patients tolerate certain therapeutics while others suffer terrible side effects from them?
Increasingly, the answer to both questions appears to be "metabolomics." Our response to cancer medications -- positive or negative -- is determined by our genes. Scientists are now hard at work trying to understand these connections so that the medical profession can make earlier, better informed treatment decisions and provide patients with the best prospects for success.
At the forefront of that research is a team of researchers at Inselspital University Hospital a teaching hospital associated with the University of Bern in Switzerland. Although its origins go back to 1354, Inselspital is a distinctly modern institution employing a staff of 7,255, providing care for 250,000 patients each year, and delivering training to 600 medical students and more than 1,000 other healthcare professionals.
Drs. Carlo Largiader, Martin Fiedler, and Jean-Francois Dufour of Inselspital’s Center for Laboratory Medicine are studying the influence of genetic variation on drug response. The team's primary research project is focused on the polygenic basis of variable response to the chemotherapeutic drug 5-fluorouracil (5-FU), one of the most commonly prescribed agents for the treatment of solid cancers.
Although it is used to treat approximately two million patients worldwide per year, 5-FU causes severe toxicity among 10-15% of patients. The Inselspital team is working to develop pre-treatment tests to identify patients at risk of severe toxicity by 5-FU and by co-administered drugs, and thus, to contribute to a more individualized administration of these medications. Ultimately, the group seeks to translate scientific knowledge into clinically useful genetic and pharmacological markers for individualized drug prescription, and thus, to contribute to treatments tailored more closely to patient needs.
In conjunction with their selection for the Centers of Innovation Program, Waters recently had the opportunity to speak to Drs. Largiader, Fiedler and Dufour ..
Please tell us about your specialty and your role within Inselspital.
CARLO LARGIADER: I’m the Vice-Director of the Institute of Clinical Chemistry. My research specialty is pharmacogenetics, and more recently, pharmacometabolomics, which tries to combine the two approaches. In the pharmacometabolomic-informed approach, you go from phenotypic information back to the genes.
MARTIN FIEDLER: I’m a clinician, and I started my clinical career at the University Hospital in Gottingen in 1992. I worked in the field of nephrology and intensive care medicine, and in 2000, I moved to Leipzig, switched fields, and started with laboratory medicine and proteomics. We worked with MALDI-TOF and tried to find some new biomarkers in patients with pancreatic cancer. Then we moved to metabolomics and since 2011, I’ve been Director for the University Institute of Clinical Chemistry, and now at the Center of Laboratory Medicine.
JEAN-FRANCOIS DUFOUR: I studied medicine in Geneva, moved to Bern in ’97, went to the US for several years, where I trained in gastroenterology and hepatology. Since 2011, I have headed the hepatology department here in Bern. I am one of the co-directors of the University Clinic for Visceral Surgery and Medicine. We have the oldest and the biggest liver unit in Switzerland, and my research interests include non-alcoholic fatty liver disease and hepatocellular carcinomides. Here also, metabolomics is already playing a big role.
What is the mission of the Institute of Clinical Chemistry?
CARLO LARGIADER: The primary mission is one part services, one part teaching, and one part research, all in the field of laboratory medicine. Last summer, the labs of clinical chemistry, hematology, and immunology were merged into the Center of Laboratory Medicine, so we are the central lab in the hospital, but also a hub for research facilities. The metabolomics facility is one of our platforms. We also run the institutional biobank of the hospital, which provides a resource for research for all the clinicians here in the hospital, and also for a network of biobanks in Switzerland.
Tell us more about the biobank and its purpose.
CARLO LARGIADER: The biobank consists of two areas of action. One is the institutional biobank, where we intend to collect samples from all in-patients, which should give us a good baseline of samples for various research projects, specializing in high-quality samples, which are adequate for mass spectrometry analysis. The second area is to provide these services for specific studies. We are working to leverage the lab where we have the infrastructure for the pre-analytics to also do the analytics with the samples.
Which instrumentation are you currently using in the laboratory?
CARLO LARGIADER: For the non-targeted analysis, we have a Waters SYNAPT-G2, and we have four Waters Xevo-TQS systems for the routine work. The routine work is mostly for immunosuppressants, then we have vitamin D, steroids, aldosterone, and acylcarnitines profiles. Most of the instruments are used for research projects, where we handle requests to develop assays for specific markets. A large number of our projects consist of non-targeted work, where people are interested in finding new candidates, or candidate pathways, in very diverse research questions.
Tell us more about assays you've developed for other biomarkers or targets.
CARLO LARGIADER: One example is the bile acid that was requested from gastroenterology, as a marker for resorption disorders. This is one that is now offered to the clinic, and which may be a promising marker in the future for this application. For the non-targeted assays, an example is prostate cancer. People are interested in separating low-risk cancer types from high-risk cancer types based on metabolomic profile. This could help them recognize which tumors need to be operated on, and which do not. We have preliminary data, and at least on these very well-defined, discrete phenotypes, it’s indeed possible to separate them.
Dr. Dufour, what is unique about the clinic for Visceral Surgery and Medicine.
JEAN-FRANCOIS DUFOUR: This is a clinic that merges three specialties: visceral surgeons, gastroenterologists, and hepatologists. I supervise everything that has to do with the liver, and we have a colleague for gastroenterology, and the visceral surgeons with us. Our mission is to provide the best care for our patients. We also have teaching activities, training younger physicians, and research activities in the clinic itself for clinical studies and in the laboratory for basic research.
How would you characterize your partnership with Waters?
MARTIN FIEDLER: It’s very important for us to have a good partnership with a company like Waters that can help us have success with new technologies and solutions. The biggest problems today are getting more automation for the clinical work, and handling the immense amount of data being generated in non-targeted assays.
What challenges remain for the future of healthcare?
JEAN-FRANCOIS DUFOUR: I think we are on the verge of having many, maybe too many, possibilities for our patients. We have to be able to choose which is the best one for a specific patient. For example, if you take cancer, there are many drugs targeting several pathways, very specific enzymes in these pathways. These drugs are very expensive. They have side effects. What we do right now is to treat the patient and see what happens, and measure an effect after weeks or months. If we can determine beforehand who will respond to the treatment, who will not, who will have side effects, who will not have side effects, that will be a big improvement for our patients' quality of life, and for the cost of these treatments.
When it comes to personalized medicine, where do you see the most opportunity?
JEAN-FRANCOIS DUFOUR: One area that's very active for this is cancer, definitely. But I also think that it will come for metabolic diseases.
MARTIN FIEDLER: I think the most progress in the past was focused on the field of genomics, in terms of next-generation sequencing, and so on. But what we need is more progress in the field of metabolomics and other biomarkers. There’s has not been real progress in biomarkers in the field of laboratory medicine. Most biomarkers now today are focused on the field of tissue -- in the tissue -- the field of pathology, but not in the field of laboratory medicine. So there’s a gap in this field. I hope we can bring the different ‘omics technologies together, especially pharmacogenomics with pharmacometabolomics and so on. That is what is missing today.
