Specialization
Inborn errors of metabolism, Enzymology, Pharmacogenetics, Lysosomal storage disorders, Purine and Pyrimidine metabolism
Focus of research
The main lines of research are:
- Inborn errors of metabolism.
- Pharmacogenetic consequences of defects of the pyrimidine degradation pathway.
- Biochemical aspects of pediatric oncological diseases
Background and aim of research theme
The research of my group has been centred around the role of metabolism in genetic (malignant) diseases, to develop strategies to diagnose and treatment of new patients.
(1) Pharmacogenetic aspects of inborn errors of metabolism
A particular focus of my group has been the pharmacogenetic aspects of inborn errors of metabolism and we are involved in various national and international studies. Our research efforts have been instrumental in identifying novel genetic mechanisms underlying severe fluoropyrimidine toxicity and we have developed a novel in vivo loading test to diagnose cancer patients at risk. This test is now part of the routine diagnostic procedures in several hospitals in the Netherlands.
(2) Novel Inborn errors of metabolism
My group has been instrumental in the discovery of disease-causing genes in patients with rare Mendelian diseases. Using a detailed clinical and biochemical phenotyping approach, combined with whole genome sequencing our team of clinicians, functional lab specialists, and bioinformaticians identified an expansion of a GCA-repeat tract of the gene encoding glutaminase (GLS) in 3 unrelated patients with progressive ataxia and early onset developmental delay (Published in NEJM). Furthermore, we have been the leading group in the identification of a novel inborn error of pyrimidine metabolism, a hCNT1 deficiency resulting in altered pyrimidine nucleoside homeostasis. Finally, we have identified the first cytosolic Fe-S cluster protein assembly disorders associated with lethal neurodegeneration.
(3) Catecholamine metabolites associated with clinical and genetic characteristics of neuroblastoma
Neuroblastoma is a paediatric malignancy of the developing sympathetic nervous system that is characterised by increased production and excretion of catecholamine metabolites. We have shown that analysis of a urinary panel of eight catecholamine can improve neuroblastoma diagnostics and risk assessment. We have identified 3-methoxytyramine as powerful prognostic marker and predicting MYC activity in the tumour. Our findings have gained considerable attention from other international groups. For this reason, A European prospective study, including patients from 15 different countries was designed in order to validate and extend our knowledge regarding the clinical implication of catecholamine metabolites in neuroblastoma.
Brief outline of plans for research in the next five years
My ambition is to elucidate the role of metabolism in genetic (malignant) diseases and to develop therapeutic strategies to prevent, attenuate, or cure these conditions.
(1) Pathophysiology and therapeutic development of inborn errors of pyrimidine metabolism
Inborn errors of purine and pyrimidine metabolism are associated with a broad spectrum of clinical abnormalities. We are the referral centre for pyrimidine degradation defects and one of our goals will be to study the pathophysiology in detail using a DPYD knockout mouse model which was developed by our group in collaboration with the “Institut Clinique de la Souris” in France.
(2) Pathophysiology and therapeutic development of new inborn errors of metabolism
The first inborn error of metabolism (IEM) caused by a short tandem repeat (STR) expansion in GLS was published by our group. The pathogenic mechanisms of such glutaminase deficiency caused by this complex molecular aberration is not yet known. In a collaboration between three University Medicals Centers, which have specific expertise regarding the functional aspects of repeat-expansions disorders and/or genetic metabolic diseases, we will execute an innovative fundamental research project which will help to elucidate the pathological mechanism(s) and the development of therapy and optimal care tailored to the individual patient.
In parallel, we will investigate the pathogenic mechanisms of the first two inborn errors of iron-sulfur cluster biosynthesis, as identified by our group, together with an international consortium, to identify therapeutic targets.
(3) Onco-metabolomic analysis of neuroblastoma
Neuroblastoma is the most common solid extracranial tumor in children. The relative paucity of recurrent somatic mutations in neuroblastoma challenges therapeutic strategies that rely on frequently altered oncogenic drivers. The insight that many cancer-related pathways have profound effects on metabolism and that many tumors become dependent on specific metabolic processes has boosted interest in targeting cancer metabolism as a promising therapeutic rationale. In collaboration with dr. G.A.M. Tytgat from the Princess Maxima Centre, we will characterize the metabolic profile of neuroblastoma to identify key-metabolites and pathways, in particularly those associated with MYCN amplification. In addition, metabolic signatures might reveal new therapeutic targets and/or predict the likelihood of patients to respond to therapy and outcome.
The goal of this project is to bring the detection of neuroblastoma-associated metabolites to the clinic, thereby improving diagnosis, risk stratification, and response assessment, as well as identifying key metabolic targets.
Specifically, we will:
1. Validate and implement our catecholamine panel in an international prospective multicentre study;
2. Identify a neuroblastoma-specific metabolic profile and key metabolic pathways using both targeted and untargeted metabolomics; and
3. Bridge the gap between catecholamine excretion profiles, metabolomics,and genetic profiles using paired samples obtained from neuroblastoma patients.