Project information:
Knockout and transgenic mouse models have proved to be invaluable tools to elucidate factors that affect the susceptibility to (anticancer) drugs, toxins, and carcinogens. The Schinkel group has generated a unique collection of knockout and humanized transgenic mouse strains for genes that affect the behavior of these exogenous compounds, as well as endogenous compounds. These include mice that are knockout and/or transgenic for:

• Active multidrug efflux transporters like P-glycoprotein (ABCB1) and BCRP (ABCG2).
• Multispecific drug uptake transporters (e.g., OCT1-3, OATP1A/B).
• Multispecific drug metabolizing enzymes of the CYP3A and CES families.
• Combinations of the above to study their functional interactions.

Variation in activity of these so-called detoxifying systems due to genetic polymorphisms, or inhibition or induction by co-administered drugs or dietary compounds can result in dramatic alterations in the behavior of drugs. This can lead to altered resistance or susceptibility of tumors to chemotherapy, or to increased or decreased toxic side effects for the patient. As a consequence, these detoxifying systems are major players determining the therapeutic efficacy of drugs. Basic insights into the functioning of these systems obtained using the genetically modified mouse strains can be of great help in optimizing drug therapy in patients.

In addition to their roles in drug handling, these detoxifying systems also often have strong effects on the behavior of lipids, for which they also appear to have detoxifying functions. As a consequence, disruption of their function often results in obesity, increased levels of cholesterol and other lipids in blood, liver and adipose tissue, inflammation, and type 2 diabetes phenotypes, collectively known as “metabolic syndrome”. Metabolic syndrome is a major factor in the development of cardiovascular disease and type 2 diabetes, and thus in morbidity and mortality seen in developed societies.   

The aim of this project is to reach a better understanding of why these drug detoxifying systems often have this dual functionality in drug and lipid detoxification. For this purpose we will both perform pharmacological experiments, often with experimental anticancer drugs, and physiological experiments addressing the mechanistic background of the metabolic syndrome phenotypes. For the latter purpose we will for instance study the effects of modified diets, and/or analyze physiological changes using for instance clinical chemistry, histological, RNAseq and proteomics analyses.  

We hope that the results of these studies will both help in improving the development of new (anticancer) drugs, and increase our understanding of the factors contributing to the susceptibility to metabolic syndrome symptoms.  

This project is part of a larger collaborative research program at the Netherlands Cancer Institute, aimed at understanding and predicting the in vivo behavior of drugs, toxins and carcinogens. As we have demonstrated before, this knowledge can be translated into clinical applications to improve current chemotherapy and pharmacotherapy strategies. The person to be hired will participate in a team of 5 to 6 people working on related research lines. 

We are seeking a highly motivated candidate with a strong background in medical biology or related areas and an interest in in vivo physiological and pharmacological research questions.

Animal experimentation forms an essential part of this project. Applicants should have, or be willing to obtain, an “Article 9” permit for the design and execution of animal experiments.

Fixed-term contract: 3 years.

The temporary employment will be for a period of 3 years. The gross salary per month will be from € 3.995,- to € 4.391 according to the FWG-function group 55, depending on previous experience. 

The terms of employment will be in accordance with the CAO Ziekenhuizen.

The Netherlands Cancer Institute is among the world’s best comprehensive cancer centers, combining innovative fundamental, translational, and clinical research with dedicated patient care. Our research institute gratefully acknowledges funding from the Dutch Ministry of Health, Welfare and Sport, the Dutch Cancer Society, and individual donors.