1. Drug rediscovery- making old drugs new.

In the 1940s and 1950s, Nobel Laureates Gertrude Elion and George Hitchings developed various agents with the intention to treat and possibly cure cancer. One of the first compounds, was thioguanine (1950), a thiopurine-derivative effective in inhibition of the growth of leukemic cells. Afterwards, additional thiopurine-derivatives, i.e. mercaptopurine (1951) and azathioprine (1957), were developed to broaden treatment options, and were subsequently explored for the management of immune and inflammatory disorders. The thiopurines mercaptopurine and azathioprine are considered mainstay immunosupressive therapy in inflammatory bowel disease  since the 1990s, however drug survival is limited as almost half of the patients cease therapy within the first year. This high drop-out rate is mainly explained by the development of intractable adverse events or toxicity.

My research line mainly focusses on the optimization of thiopurine therapy in IBD.

1. Pharmacology, effectiviness and toxicity of thioguanine (currently off-label indication) as an escape thiopurine after failure of mercaptopurine and/or azathioprine

2. Optimization of thiopurine therapy by therapeutic drug monitoring (measurement of 6-thioguaninenucleotides and 6-methylmercaptopurine)

3. Coordinating two national registers of thioguanine therapy in an attempt to unconditionally register thioguanine as an offical treatment option for IBD (drug rediscovery). This project is in conjunction with the College ter Beoordeling van Geneesmiddelen.

4. Development of a novel method (LC-MS/MS) to measure thiopurine metabolites in stool samples, as recent insights revealed that colonic bacteria are able to metabolize thioguanine into the pharmacologically active metabolites, paving the way for potential future topical thiopurine therapy (for example colonic-release thioguanine) in inflammatory bowel disease patients. This topical therapy avoids the development of systemic toxicity/adverse events.

2. Volatile organic compounds/electronic nose technology

 The overall metabolic state of an individual is reflected by emitted volatile organic compounds (VOCs), which are gaseous carbon-based chemicals. VOCs are detected by our sensory olfactory nerves and form the molecular basis for our sense of smell. As such, we emit our own individual odor fingerprint or so-called smellprint. This may change over time in response to any alteration in metabolism such as modifications caused by gastrointestinal infection, inflammation, external factors such as medication and diet, or development of neoplastic disease such as colorectal cancer. This means that analysis of VOCs can provide a fully noninvasive metabolomics biomarker profile that could be used as a diagnostic or follow-up tool.

My second research essentially line focusses on the application and optimization of VOC analysis in gastroenterology.

1. The potential of fecal VOCs as fully noninvasive markers for the detection of colorectal cancer and its precursor lesions (adenoma) by electronic nose technology.

2. The potential of fecal VOCs for the diagnosis and prediction of disease course in inflammatory bowel disease patients

3. Exploring the origin of fecal VOCs by integration of fecal proteome, amino acids and microbiome in patients with colorectal cancer/adenoma