Prof. Ines Thiele, researcher at the Luxembourg Centre for Systems Biomedicine (LCSB) at the University of Luxembourg has been selected for the highly prestigious research funding of the European Research Council (ERC). The head of the LCSB group “Molecular Systems Physiology” and ATTRCT fellow of the Fonds National de la Recherche (FNR) has been awarded an “ERC Starting Grant” for her project “Bug the Drug”. Ines Thiele’s project is to develop novel computer models that will assist in the personalisation of drugs used in cancer therapy or for treating Parkinson’s disease, so that the best drug for each individual patient can be prescribed. The basis for the models will be data on the patients’ dietary habits and the composition of their bacterial gut flora. This should help to reduce side effects and intolerances. The distinguished project will be funded with 1.6 million euros over a period of five years.

Currently, in most cases, a drug will be prescribed based on the experience and assessment of the treating physician. The physician’s prescription is very often right and thus helps the patient return to a healthier condition. But there are also cases when a person does not respond to a certain drug as desired, or has severe side effects to it. Especially in the case of life-sustaining or complex therapies – for example when fighting tumours or treating neurodegenerative diseases such as Parkinson’s – both the patient and the physician would certainly like to employ the best, most effective drug.

Prestigious ERC Grant

To make a leap forward in this respect is the goal of the ERC-funded project of Prof. Dr. Ines Thiele. So-called physiology-based pharmacokinetic models have already existed for some years that can quite accurately predict how an active pharmaceutical ingredient will be taken up, transported, converted and excreted again by the body. However, these models only ever look at groups of people, and never the individual. “We want to change that,” declares Thiele. “We will develop novel computer models that factor in the dietary habits of individual patients and the composition of their bacterial gut flora, the microbiome. This is because there are important metabolic processes taking place in the gut that can alter the success and lead to a failure of a drug treatment.”

In order to determine this influence of the microbiome, Thiele will first concentrate on the action of a drug for treating colon tumours and another drug used in Parkinson’s therapy. “The cancer drug we want to study is both activated and detoxified in the liver,” Thiele says. “These two processes ensure that, in most people, the drug arrives in the intestine at the right dose to destroy the tumour. Some patients, however, have bacteria in the gut whose metabolic activity reactivates the detoxified fraction of the drug. The resulting excessive drug dose then triggers severe diarrhoea.” With the help of new computer models that factor in the metabolic activity of the gut bacteria, Thiele and her team want to identify indicator substances in the blood, so-called biomarkers, that will reveal in a blood test whether a cancer patient will have an intolerance to the drug. “Then, those drugs that the patient can tolerate would be prescribed from the beginning – and the diarrhoea avoided.”

The part of the project concentrating on a drug for treating Parkinson’s disease focuses on the patient’s dietary habits. Levodopa is the name of the substance that Parkinson’s patients take to alleviate tremors and other symptoms of the disease. “Levodopa is very similar to certain components of protein that come from food. The food and drug compete in the gut to be absorbed into the blood stream, and in the brain to enter the brain tissue,” Thiele explains. “With the new models we are going to develop, we want to determine the composition of those competing protein components that get into the patient’s blood from what he eats. Once we know that, we can give nutritional recommendations that reduce the amount of these proteins in the diet – and thus increase the body’s capacity to absorb Levodopa.”

Treating intestinal cancer and Parkinson’s disease

The drugs for treating intestinal cancer and Parkinson’s disease are two active pharmaceutical ingredients that Thiele wants to study particularly intensively in the computer models she will be developing. “We will use these to show in principle that our method of computer-based, patient-specific tolerability testing is possible,” Thiele says. “After that, however, we will widen the focus and build models for a total of 30 different drugs.”

Prof. Dr. Rudi Balling, the director of LCSB, is delighted at Thiele’s success in the highly competitive ERC process. “For one thing, Ines Thiele’s ERC Starting Grant shows that, with her, we have a truly outstanding scientist at LCSB who has immense competence in the field of modelling biological systems. For another, it is an endorsement of our strategy to analyse such systems not only in the lab but also with the help of computer models. This dual approach carries us most effectively forward on the path towards better understanding widespread diseases like cancer or neurodegeneration and treating them more effectively.” Thiele´s ERC grant is a new formidable success for the LCSB and Luxembourg, as Marc Schiltz, Secretary General of FNR points out: „This ERC grant is an international recognition of the excellence and research quality achieved in our country and it gives additional credibility to the FNR’s strategy that aims to attract the best researchers to Luxembourg in key research areas thanks to its programmes FNR PEARL and FNR ATTRACT.“ And Ines Thiele adds: “I am very grateful for the excellent support from the ATTRACT fellowship program by the FNR as well as the supportive environment by the Luxembourg Centre for Systems Biomedicine. Their continuous support permitted to build an internationally competitive research program.”

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