Molecular markers: predicting the most effective treatment for IBD

Inflammatory bowel disease (IBD) is a group of disorders that cause chronic inflammation in the intestine. Early effective treatment can help manage this condition and improve the quality of life of patients. The research project “Longitudinale Spatial Proteogenomik zur Charakterisierung von Remission bei Colitis ulcerosa” (English: Longitudinal and Spatial Proteogenomics to Decipher Remission in Ulcerative Colitis) aims to identify molecular markers to better assess the chances of success of certain biological therapies and subsequently determine the best individualized treatment plan.

Dr. Florian Tran is leading the research project. His work is made possible by an Else Kröner Memorial Fellowship. In this MEDICA.de interview, the clinician scientist reveals what the award means for him and his research and explains the role transcriptomics plays in this setting.

You are the recipient of an Else Kröner Memorial Fellowship. What does this support mean to you personally?

Dr. Florian Tran: This funding means that I have two years of protected research time that allows me to dedicate my time fully to the funded research project. This support is also an important personal success. It is one of my first most notable personal grants in a competitive process from a large foundation such as the Else Kröner-Fresenius-Stiftung.

What prompted you to research inflammatory bowel diseases with a focus on ulcerative colitis as part of your research project?

Tran: I have always been interested in the function of the gastrointestinal tract beyond digestion and nutrient absorption. Chronic inflammatory diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel diseases (IBD) are still on the rise worldwide and are sometimes difficult to treat. Mismanagement of these chronic conditions can dramatically restrict the quality of life and put a patient's long-term health at risk. In the working groups of Prof. Schreiber and Prof. Rosenstiel, we are researching the response to IBD treatment. We examine why some patients benefit from (biologic) therapies and why others do not.

In the funded project, we are initially focusing on one disease, namely ulcerative colitis. With ulcerative colitis, the diagnostic advantage is that it’s primarily the distal sections that are affected and that the samples are collected from similar intestinal regions. That’s why we can carry out the scheduled assessments on fairly standardized biosamples.

With Crohn’s disease, the other IBD, the localization of the inflamed bowel sections is much more variable, making a standardized characterization more difficult. The intermediate goal is to apply the techniques we use here to also study Crohn’s disease in the future.

What role does transcriptomics play in this setting?

Tran: Transcriptomics (= entirety of gene expression) of tissues is one of several molecular levels one can examine pertaining to individual treatment response. Various working groups - including our working group - were able to show that certain signatures in the transcriptome can partly predict the response to therapy. However, this prediction was not accurate enough and the signatures in the colonic tissue were never validated in multiple independent studies.

My project aims to apply the technique of spatial proteogenomics, i.e., transcriptomics and proteomics combined with spatial resolution. This new method enables us to work with molecular signals in a considerably higher resolution: We could image and analyze the transcriptome of individual cells in their exact location on a tissue sample.

How can this affect the treatment of inflammatory bowel diseases?

Tran: We believe that transcriptomics and proteomics will allow us to identify previously undetected signatures that can predict the therapeutic success in the context of biological therapy. Receiving the right treatment at an early stage benefits the patient the most. On the one hand, this would spare the treating physicians and patients from embarking on a long-term yet unsuccessful treatment, comprising the related restrictions in quality of life and the increased risk of medical complications. On the other hand, we now know that every prior failed biological therapy reduces the success probability of the next biological therapy.

If we could fast forward two years, what would you like to say about the two years you dedicated to your research?

Tran: I want to be able to say it was worth the time spent, and I am truly optimistic that it will be, meaning we can apply the new methods to decode potential new signatures. That being said, these molecular markers must then be replicated in independent studies using less complicated methods. It’s the only chance that our work will ultimately support the establishment of a clinically relevant marker set that helps the treating physicians choose the particular IBD treatment that is most successful for the individual patient.