Research interests

The main lines of research are:

  • Inborn errors of purine and pyrimidine metabolism.
  • Pharmacogenetic consequences of defects of the pyrimidine degradation pathway.
  • Biochemical aspects of pediatric oncological diseases

Background and aim of research theme

Inborn errors of pyrimidine metabolism and the pharmacogenetic consequences
Inborn errors of purine and pyrimidine metabolism are associated with a broad spectrum of clinical abnormalities including anemia, immunodeficiency, nephrolithiasis, convulsions, autism and psychomotor retardation. Pyrimidine nucleotides are essential for a vast number of biological processes such as the synthesis of RNA, DNA, phospholipids, glycogen and the sialylation and glycosylation of proteins. There is, however, an increased awareness that pyrimidines play an important role in the regulation of the central nervous system and that metabolic changes affecting the levels of pyrimidines may lead to abnormal neurological activity. Patients with a defect in one of the enzymes of the pyrimidine degradation pathway often present with a neurological disorder but a considerable phenotypic variability has been reported among these patients. In addition, the same defects can lead to severe life-threatening toxicities when (partially) deficient individuals are treated with the pyrimidine analogue 5-fluorouracil. To date, the pathological mechanism underlying the various clinical abnormalities is not known. The main goal of our research is to elucidate the role of enzymes of purine and pyrimidine metabolism and the altered homeostatis of substrates and products in health and disease.


Biochemical and clinical aspects of neuroblastoma

Neuroblastoma is derived from precursor cells of the sympathetic nervous system and it is the most common extracranial solid tumour of childhood. The prognosis for children suffering from neuroblastoma is highly dependent on the age at diagnosis and the stage of the disease. Patients suffering from metastasized neuroblastoma with amplification of the MYCN oncogene, which is found in approximately 20% of primary, predominantly metastasized neuroblastomas, have a very poor prognosis with a survival rate of approximately 10-25%.
The clinical diversity of neuroblastoma correlates with several characteristic molecular features observed in neuroblastoma, including amplification of the MYCN oncogene and activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway]. However, patients with the same risk assessment, and thus receiving the same treatment, can have markedly different clinical courses. Therefore, the identification of more specific and sensitive markers for response to therapy and outcome prediction is required.

Signal transduction pathways associated with cancer progression and chemotherapeutic resistance are increasingly being investigated as molecular targets of chemotherapy. There is now compelling evidence that the PI3K/Akt pathway plays an important role in regulating the bioavailability of key-proteins, such as N-myc in neuroblastoma. Therefore, inhibition of the PI3K/Akt pathway in neuroblastoma might be accompanied by profound effects on cell proliferation and viability neuroblastoma cells. In addition, PI3K inhibitors might increase the efficacy of chemotherapeutic drugs which are currently being used in the treatment of neuroblastoma. The discovery 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. There are currently several drugs under development or in clinical trials that are based on specifically targeting the altered metabolic pathways in tumours. To date, little is known about the impact of MYCN and the PI3K/Akt pathway on the metabolic profile in neuroblastoma.

In 90-95% of neuroblastoma patients, the urinary concentrations of catecholamines and their metabolites are strongly elevated and provide an important non-invasive diagnostic tool for diagnosis, during treatment and at follow up. To date, different types of catecholamines and/or their metabolites, such as vanillylmandelic acid (VMA) and homovanillic acid (HVA) are being used for diagnosis and follow-up of neuroblastoma patients. However, conflicting data are available regarding their diagnostic sensitivity and their significance with respect to clinical outcome. Only sporadic data is available for the other catecholamines and their metabolites with respect to clinical and genetic characteristics.

The main goal of our research is

  • To develop new and effective therapeutic strategies using inhibitors of the PI3K pathway.
  • Characterization of the metabolic profile of neuroblastoma cell lines to identify key-metabolites and key-pathways, in particular those associated with MYCN amplification and PI3K/Akt signaling. These the metabolic profile might reveal new therapeutic targets.
  • To identify the optimal panel of catecholamines, metanephrines and phenolic acids for the diagnosis and prognosis of patients with a neuroblastoma.
  • To investigate the genetic mechanisms that are associated with catecholamine excretion profiles in neuroblastoma



Clinical Biochemical Geneticist

ID: 97765