PhD A.B.P. van Kuilenburg

foto

PhD A.B.P. van Kuilenburg

Position
MD-PhD
Main activities
Patient care, Research
Specialisation
Clinical Biochemical Geneticist
Focus of research

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

 

Key publications
  • van Kuilenburg André B. P., Häusler Peter, Schalhorn Andreas, Tanck Michael W. T., Proost Johannes H., Terborg Christoph, Behnke Detlev, Schwabe Wolfgang, Jabschinsky Kati, Maring Jan Gerard Evaluation of 5-Fluorouracil Pharmacokinetics in Cancer Patients with a c.1905+1G > A Mutation in DPYD by Means of a Bayesian Limited Sampling Strategy Clinical pharmacokinetics 2012;51 (3):163-174 [PubMed]
  • van Kuilenburg André B. P., Meinsma Rutger The pivotal role of uridine-cytidine kinases in pyrimidine metabolism and activation of cytotoxic nucleoside analogues in neuroblastoma BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE 2016;1862 (9):1504-1512 [PubMed]
  • van Kuilenburg André B. P., Meijer Judith, Tanck Michael W. T., Dobritzsch Doreen, Zoetekouw Lida, Dekkers Lois-Lee, Roelofsen Jeroen, Meinsma Rutger, Wymenga Machteld, Kulik Wim, Büchel Barbara, Hennekam Raoul C. M., Largiadèr Carlo R. Phenotypic and clinical implications of variants in the dihydropyrimidine dehydrogenase gene BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE 2016;1862 (4):754-762 [PubMed]
  • van Kuilenburg André B. P., Dobritzsch Doreen, Meijer Judith, Krumpel Michael, Selim Laila A., Rashed Mohamed S., Assmann Birgit, Meinsma Rutger, Lohkamp Bernhard, Ito Tetsuya, Abeling Nico G. G. M., Saito Kayoko, Eto Kaoru, Smitka Martin, Engvall Martin, Zhang Chunhua, Xu Wang, Zoetekouw Lida, Hennekam Raoul C. M. beta-Ureidopropionase deficiency: Phenotype, genotype and protein structural consequences in 16 patients BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE 2012;1822 (7):1096-1108 [PubMed]
  • van Kuilenburg André B. P., Largiadèr Carlo R. SNPs and Haplotypes in DPYD and Outcome of Capecitabine-Letter Clinical cancer research 2011;17 (17):5837; author reply 5835-5837; author reply 5836 [PubMed]
All Publications
Curriculum Vitae

Co-promoter of Eight theses:

  1. A.A. van den Berg: “The Metabolism of Pyrimidine Ribonucleotides as a Target of Acute T Lymphocytic Leukemia” (November 1995).
  2. R.J. Slingerland: “Ribonucleotide Metabolism of Neural Crest Derived Cancer Cells” (November 1996).
  3. J. Cornelissen: “The effects of MIBG and HBO on Neuroendocrine Cell Lines” (October 1997).
  4. A.C. Verschuur: “Modulation of pyrimidine nucleotide synthesis in pediatric leukemia: a pivotal role for CTP synthetase” (December 2000).
  5. J. Bierau: “The pivotal role of CTP synthetase in the metabolism of (deoxy)nucleosides in neuroblastoma” (May 2003).
  6. A.J.M. de Ruijter: “Characterization of the effects of a novel histone deacetylase inhibitor, BL1521, on neuroblastoma cells” (June 2005).
  7. R. Cuperus: “Modulation of fenretinidie induced cell death in neuroblastoma” (October 2014)
  8. M.C. van Staveren: "DPD screening to prevent toxicity in Fluoropyrimidine treated patients (November 2016)

Current PhD projects

  • O. Besancon: Pre-clinical screening of drug combinations for neuroblastoma. Optimising current treatment modalities through targeting the PI3K/Akt pathay.
  • I.R.N. Verly: Catecholamine excretion in neuroblastoma: identification of catecholamine metabolites profiles associated with clinical and genetic characteristics of neuroblastoma.


Parameters of esteem:
Opponent of 7 national and 5 international PhD theses:
 

National PhD theses

  • Opponent of O.H. Temmink on his thesis entitled: “Role of thymidine phosphorylase/platelet- derived endothelial cell growth factor inhibition in the cytotoxicity of fluoropyrimidines”, (3-10-2007), Free University of Amsterdam, Amsterdam, The Netherlands.
  • Opponent of R.H. Houtkoper on his thesis entitled: “Cardiolipin metabolism in Barth syndrome”, (24-03-2009), University of Amsterdam, Amsterdam, The Netherlands.
  • Opponent of drs. Jaap A. Bakker on his thesis entitled:: Metabolic and genetic aspects of thiopurine metabolism, (27 Oktober 2010), University of Maastricht, Maastricht, the Netherlands.
  • Opponent of drs. Giovanni-Codacci Pisanelli on his thesis entitled: “Biochemical Modulation of 5- fluorouracil by uridine and leucovorin” (23 November 2012), Free University Amsterdam, Amsterdam, the Netherlands.
  • Opponent of drs. Marli Dercksen on her thesis entitled: Ïsovaleric academia: an integrated approach toward predictive laboratory medicine” (19 September 2014), University of Amsterdam, Amsterdam, the Netherlands.
  • Opponent of drs. Linda van der Tol on her thesis entitled: "Fabry or not Farby, from genetics to diagnosis" (April 2015).
  • Opponent of drs. Bart Jacobs on his thesis “Methods for improving the safety of fluoropyrimidine anticancer drugs” (november 2016).

International PhD theses

  • Selected as sole opponent of An van Rompay on her thesis entitled: “Identification and characterization of nucleoside and nucleotide kinases, pharmacological activation of anti-cancer and anti-viral nucleoside analogs”, (5-4-2001), Karolinska Institutet, Stockholm, Sweden.
  • Selected as sole opponent of Mia Bjerke on her thesis entitled:”Nucleoside analog toxicity and nucleoside kinase deficiency; effects on mitochondrial DNA” (26-9-2008), Karolinska Institutet, Stockholm, Sweden.
  • Opponent of Annelies Bronckaers on her thesis entitled: “Thymidine phosphorylase (TP) and TP inhibitors in angiogenesis and fluoropyrimidine metabolism”, (17 September 2009), Catholic University Leuven, Leuven, Belgium.
  • Opponent of drs. Johan vande Voorde on his thesis entitled: “The effect of catabolic mycoplasma enzymes on the therapeutic efficiency of nucleoside analogues” (2 December 2013), KU Leuven, Leuven, Belgium.
  • Opponent of drs. Christof Vulsteke on his thesis entitled: “The impact of germline genetic variability on chemotherapy-induced toxicity and survival in early breast cancer patients”(15 October 2015), University of Antwerpen, Belgium.

Prices and awards

  • Coauthor of the first prize award for the best communication at the 5th International Symposium "Genetics, Neurobiology and Nutrition in Human Disease", Coral Gables, 5-7 December 1994, Miami, Florida, USA.
  • Coauthor of the Aids Research Amsterdam (ARA) award for the best article published in 1996 regarding the research on aids: Back, N.K.T. et al. EMBO J. (1996) 15, 4040-4049.
  • Second prize award for the best poster at the 55th meeting of the Dutch Society of Clinical Chemistry, 25-26 April 2002, Lunteren, The Netherlands: Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil. Frequency of the common IVS14+1G>A mutation causing DPD deficiency.
  • Coauthor of the first prize award for the best poster at the EKZ wetenschapssymposium, 21 January 2010, Amsterdam. Promising effects of the PI3K/ mTOR inhibitor PI-103 with chemotherapeutic drugs on human neuroblastoma cell lines.

Miscellaneous

  • Selected as a member of the Scientific Committee of the Purine and Pyrimidine Society (2003).
  • Guest Editor of the Proceedings of the joint 11th International and 9th European Symposium on Purines and Pyrimidines in man (2004).
  • Elected as secretary of the ESNTL [Vereniging tot bevordering onderzoek Erfelijke Stofwisselingsziekten in het Nederlands taalgebied (ESN)], 2010-2016.
  • Selected as a Member of the board of the Purine and Pyrimidine Society (PPS) (2015)
  • Professional recognition as a European Clinical Laboratory Geneticist by the European Board of Medical Genetics (2015).
  • Author of 257 scientific articles in international peer-reviewed journals and books.
  • Number of citations: > 5500
  • Hirsch-index: 34
  • Principle applicant of 24 granted projects (> €2.180.987,-)
     


Invited publications (17) and key-note lectures (18)

Invited publications:
1) Webster, D. R., Becroft, D. M. O., van Gennip, A. H., and van Kuilenburg, A. B. P. (2001) Hereditary Orotic Aciduria and Other Disorders of Pyrimidine Metabolism. In: The Metabolic and Molecular Basis of Inherited Disease. Scriver, C. R., Beaudet, A. L., Sly, W. S., and Valle, D. eds. (113), 2663-2702. New York, Medical Publishing Division, McGraw-Hill. Purines and Pyrimidines Part II.

2) Van Kuilenburg, A. B. P. and van Gennip, A. H. (2002) HPLC-Electrospray Tandem-Mass Spectrometry in Screening for Disorders of Purine and Pyrimidine Metabolism. In: Molecular testing in laboratory medicine. Bruns, D. E., Dennis Lo, Y. M., and Wittwer, C. T. eds., pp. 161- 162. Washington DC, AACC Press.

3) Bierau, J., van Kuilenburg, A.B.P. and van Gennip (2005) Nucleotide degradation. In: ENCYCLOPEDIA OF LIFE SCIENCES. John Wiley & Sons, Ltd: Chichester http://www.els.net/ [doi:10.1038/npg.els.0003908].

4) Van Kuilenburg, A.B.P. (2006) Screening for dihydropyrimidine dehydrogenase deficiency: to do or not to do, that’s the question. Cancer Invest. 24, 215-217.

5) Van Bree C, van Kuilenburg A.B.P. (2008) Will cyclopentenyl cytosine (CPEC) ever have a future in the clinic? Leuk. Res. 32, 201-202.

6) Van Kuilenburg, A.B.P., van Cruchten, A. and Abeling, N.G.G.M. (2008) Screening for disorders of purine and pyrimidine metabolisme using HPLC-electrospray tandem mass spectrometry. In: Laboratory Guide to the Methods in Biochemical Genetics. Blau, N., Duran, M., and Gibson, K.M. eds., 725-738. Springer-Verlag Berlin Heidelberg.

7) Van Kuilenburg ABP, Van Gennip AH. Beta-Ureidopropionase Deficiency. In: Lang, F (Ed) Encyclopedia of Molecular Mechanisms of Disease. Vol. 3, p. 2141. Springer, Berlin Heidelberg, 2009.

8) Van Kuilenburg ABP, Van Gennip AH. Beta Aminoisobutyrate-Pyruvate Aminotransferase Deficiency. In: Lang, F (Ed) Encyclopedia of Molecular Mechanisms of Disease. Vol. 1, p. 71- 72. Springer, Berlin Heidelberg, 2009.

9) Van Kuilenburg ABP, Van Gennip AH. Beta-Alanine-Alpha-Ketoglutarate Aminotransferase Deficiency. In: Lang, F (Ed) Encyclopedia of Molecular Mechanisms of Disease. Vol. 1, p. 53- 54. Springer, Berlin Heidelberg, 2009.

10) Van Kuilenburg, ABP, Van Gennip AH. Dihydropyrimidinase Deficiency. In: Lang, F (Ed) Encyclopedia of Molecular Mechanisms of Disease. Vol. 1, p. 533-534. Springer, Berlin Heidelberg, 2009.

11) Van Kuilenburg ABP, Van Gennip AH. Dihydropyrimidine Dehydrogenase Deficiency. In: Lang, F (Ed) Encyclopedia of Molecular Mechanisms of Disease. Vol. 1, p. 534-535. Springer, Berlin Heidelberg, 2009.

12) Van Kuilenburg ABP, Van Gennip AH. Thymidine Phosphorylase Deficiency. In: Lang, F (Ed) Encyclopedia of Molecular Mechanisms of Disease. Vol. 3, p. 2068-2069. Springer, Berlin Heidelberg, 2009.

13) Kulik W, van Kuilenburg ABP. Metabolomics Using UPLC/HPLC-Tandem Mass Spectrometry in Diagnosis and Research of Inherited Metabolic Diseases. In: Caroli S, Záray G (Eds) Analytical Techniques for clinical chemistry: methods and applications. p. 535-554. John Wiley & Sons, Inc, Hoboken, NJ, 2012.
14) Eva Gross and André B. P. van Kuilenburg. Dihydropyrimidine Dehydrogenase Deficiency and 5-Fluorouracil-Toxicity, in: Handboek of therapeutic Biomarkers in Cancer (Sherry X. Wang and J.E. Dancey, eds.) Pan Stanford Publishing, 2013, 337-351.

15) Van Kuilenburg ABP, Maring JG. Evaluation of 5-fluorouracil pharmacokinetic models and therapeutic drug monitoring in cancer patients. Pharmacogenomics. 2013 14(7), 799-811, 2013.

16) Kamatani N, Jinnah HA, Heenkam RCM and van Kuilenburg ABP. Purine and Pyrimidine Metabolism. In: Emery & Rimoin's Principles and Practice of Medical Genetics (Rimoin D, Pyeritz R, Korf B, eds.), Elsevier Science Publishing Co Inc, 1-38, 2013.

17) Bertholee D, Maring JG, van Kuilenburg AB. Genotypes Affecting the Pharmacokinetics of Anticancer Drugs. Clin Pharmacokinet. 2016 Sep 19. [Epub ahead of print].

Invited speaker (key-note lectures):

Title: Purine and pyrimidine analogues and the consequences for pharmacogenetics
Congress: Association of Clinical Biochemists Annual National Meeting ExCel
Place, date: London, United Kingdom; April 30th-May 4th 2001

Title: Clinical implications of dihydropyrimidine dehydrogenase deficiency in patients with severe 5-fluorouracil associated toxicity. Identification of new mutations in the DPD gene.
Congress: Società di Biochemica e Biologia Moleculare Italiana e Française
Place, date: Siena, Italy, September 26th-29th, 2001

Title: Dihydropyrimidine dehydrogenase deficiency: a pharmacogenetic disorder associated with severe 5-fluorouracil toxicity.
Congress: 24th Winter meeting of the EORTC-PAMM Group.
Place, data: Florence, Italy, February 5th-8th, 2003

Title: Pharmacogenetic and clinical aspects of a dihydropyrimidine dehydrogenase deficiency
Congress: 11th International and 9th European Symposium on Purines and Pyrimidines in Man
Place, data: Egmond aan Zee, The Netherlands, June 9th-13th, 2003

Title: Pharmacogenetic aspects of purine and pyrimidine analogues.
Congress: IVth Congress of the Latin American Society of Inborn Errors of Metabolism and Neonatal Screening.
Place, date: Buenos Aires, Argentina, October 26th-29th, 2003

Title: Problemen bij specifieke middelen: 5FU en DPD
Congress: 2e Themadag Nederlandse Vereniging voor Medische Oncologie
Place, date: Amersfoort, May 9th, 2003

Title: Pyrimidine degradation defects and severe 5-fluorouracil toxicity.
Congress: 4th Congress of the Federation of the European Societies (EPHAR).
Place, date: Porto, Portugal, July 17th-19th, 2004.

Title: Pyrimidine degradation defects and severe 5-fluorouracil toxicity
Congress: British Society of Gastroenterology
Place, date: Birmingham, United Kingdom, March 14th-17th, 2005

Title: The pivotal role of the pyrimidine degradation enzymes in the pathophysiology and oncology
Congress: Protein funktion auf atomarer ebene.
Place, date: Marburg, Germany, 24th May, 2005

Title: Dihydropyrimidine dehydrogenase deficiency and severe 5-fluorouracil toxicity.
Congress: 1st European Conference on Chemistry for Life Sciences
Place, data: Rimini, Italy, October 4th-8th, 2005

Title: Dihydropyrimidine dehydrogenase deficiency and toxicity of 5-fluorouracil
Congress: PAOKC Pharmacogenetics
Place, data: Rotterdam, the Netherlands, 13th March 2008

Title: The pivotal role of the pyrimidine degradation enzymes in the pathophysiology and oncology
Congress: Seminar Karolinska Institutet
Place, date: Stockholm, Sweden, 25 September 2008

Title: Pharmacogenetic aspects of 5-fluorouracil. A pivotal role for dihydropyrimidine dehydrogenase
Congress: ESF-UB Research conference in Biomedicine
Place, date: Sant Feliu, Spain, 6-11 June 2010


Title: Quel consensus pour les deficits en dihydropyrimidine déhydrogénases?
Congress: 13emes Journées de GPCO Groupe de Pharmacologie Clinque Oncologique
Place, date: Nimes, France, 25-26 November 2010


Title: Beta Oxidation Defects: How to Proceed after a Positive NBS?
Congress: VIII Latin American Congres Inborn Errors of Metabolism and Neontal Screening
Place, date: Cusco, Peru, 18-21 September 2011.

Title: The pivotal role of pyrimidine degradation enzymes in inborn errors of metabolism and oncology.
Congress: Seminar lecture University Hospital and University of Bern
Place, date: Bern, Switserland, 17 October 2011.

Title: The biochemistry and pathophysiology of purine and pyrimidine metabolism
Congress: Society for inherited metabolic disorders (SIMD)
Place, data: Asilomar, California, USA, March 9-March 12, 2014 

Title: The biochemistry and pathophysiology of purine and pyrimidine metabolism
Congress: 16th International symposium of the Purine and Pyrimidine Society
Place, data: New York, USA, 6-9 June 2015
 


 

Research programmes

PhD A.B.P. van Kuilenburg (Inborn errors of purine and pyrimidine metabolism and pediatric oncological diseases)

1) Clinical, biochemical and genetic aspects of patients suffering from a pyrimidine degradation defect.

2) Pharmacogenetic aspects associated with inborn errors of purine and pyrimidine metabolism

3) Pre-clinical screening of drug combinations for neuroblastoma. Optimising current treatment modalities through targeting the PI3K/Akt pathway.

4) Catecholamine excretion in neuroblastoma: identification of catecholamine metabolites profiles associated with clinical and genetic characteristics of neuroblastoma

Theme: Metabolic Disorders and Oncology

This research group participates in the Amsterdam Center for Metabolism

Others
R. Leen
J. Meijer
J.R. Meinsma

Prof. PhD R.J.A. Wanders (Biochemistry & Enzymology of Metabolic Disorders)

Current research funding
  • Alexion Pharma Belgium
  • Stichting Stofwisselkracht