This website uses cookies

This websites contains videos from YouTube. This company uses cookies (third party cookies). If you do not want them to use these cookies, you can indicate so here. However, this does mean that you will not be able to watch videos on this website. We also make use of our own cookies in order to improve our website. We don't share our data with other parties. Which cookies are involved?

This website uses cookies to enable video and to improve the user experience. If you do not want to accept these cookies, indicate so here. Which cookies are involved?

Ga direct naar de inhoud, het hoofdmenu, het servicemenu of het zoekveld.

Terug naar het overzicht

Groups within research area Pharmacology

AlfredSchinkel.jpg

Alfred Schinkel

Division
Pharmacology
Specialisation
Improving Drug Efficacy

Introduction

Our research focuses on genes and proteins that affect drug resistance or drug susceptibility in tumors, or influence the pharmacological and toxicological behavior of anticancer and other drugs and toxins, including carcinogens, in mice and man.

More about the Alfred Schinkel group

silhouette_geen_foto_thumb_man.jpg

Pharmacology

Division
Pharmacology
Specialisation
Research interest: Personalized Cancer Treatment

Introduction

Phase I Clinical Trials with targeted therapies
The development of anti-cancer therapies has undergone a radical change over the last decades: from conventional cytotoxic drugs that don't discriminate between normal and tumor cells, to so-called targeted therapies which inhibit a specific target within a tumor cell.
The targets are mostly comprised of receptors or tyrosine kinases that have become aberrant in tumor cells, which can cause uncontrolled cellular signaling and growth.
Within our research group, we perform many phase I studies with inhibitors of these specific targets, both in the form of small-molecule inhibitors as well as monoclonal antibodies. Since this is the first time these anti-cancer therapies are administered to humans, the main goal of these studies is to characterize the safety and pharmacokinetic profile and to determine a recommended dose for further clinical development.
In recent years, it has become apparent that these targeted therapies have relatively modest anti-tumor activity, which is mostly due to the tumor cells developing resistance through mutations in parallel cellular signaling pathways. Thus, development of these compounds has steered more towards combining these compounds.

For more information about our phase I trial unit, click here.

Pharmacodynamic assays
In support of clinical trials, our research group also focuses heavily on the development of pharmacodynamic assays, which could help us in diagnosis, but also in determining which patients benefit more from treatment.
These assays include the quantification of poly(ADP-ribose) polymerase (PARP) inhibition in peripheral blood mononuclear cells (PBMCs), which is currently validated in phase I clinical trials with the PARP-inhibitor olaparib, and circulating endothelial cells (CECs) in plasma.
Furthermore, we are in the process of validating a new assay to determine circulating tumor cells (CTCs) both in blood samples and in cerebrospinal fluid. With this assay, we could possibly detect signs of disease progression at an earlier stage.
Lastly, we are involved in optimizing assays for the determination of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) activity. These enzymes plays an important part in the metabolism and activity of fluoropyrimidines. Patients with decreased metabolism are at risk of developing serious toxicities and thus determining the DPD activity before starting treatment could warrant a dose adjustment.

Clinical pharmacology
In collaboration with our pharmacy department, our research groups conducts trials to test the safety and pharmacokinetics new oral formulations of intravenous anti-cancer drugs, such as docetaxel and paclitaxel.
Furthermore, to optimize treatment of tyrosine kinase inhibitors, we aim to develop and/or optimize therapeutic drug monitoring (TDM) for both new and existing anti-cancer treatments.
Additionally, the collaboration with the pharmacy also allows us to explore other types of pharmacological research, such as mass balance studies, measurements of intracellular metabolites of anti-cancer drugs and pharmacokinetic and pharmacodynamics modeling and simulation.

More about the Pharmacology group

Van Tellingen Liggend

Olaf van Tellingen

Division
Pharmacology
Specialisation
Brain tumors and the BBB

Introduction

Glioblastoma (GBM) is a uniformly fatal disease. The location and invasive nature of GBM renders complete surgical resection impossible. Although radiotherapy is important for disease management, side effects prohibit the delivery of curative doses. Despite the successful introduction of novel targeted therapeutics in some other solid cancer types, clinical trials in GBM have all failed. The mission of our preclinical research group is to develop and validate more effective pharmacotherapies for this disease. One of the spearheads of our research is aimed at highlighting the important role of the blood-brain barrier (BBB) in treatment failures. Although disruption of the BBB is common, this grossly affects areas of the tumor that can be surgically resected. However, the non-resectable tumor cells that have colonized the surrounding normal brain tissue are protected by the BBB and are the source of the inevitable recurrence. Just a few mainly small hydrophobic drugs display some efficacy against GBM. In particular, drug transporting proteins like ABCB1 (P-gp) and ABCG2 (BCRP) hinder the entry of most of the other effective anticancer agents, including many targeted agents. Thus, in order to develop more successful pharmacotherapy, our research aims to identify potentially useful agents that are no or weak substrates of these drug transporters. Alternatively, we are trying to improve drug penetration into brain tumors by using drug efflux pump inhibitors or carrier systems. 

Other hurdles to effective pharmacotherapies for GBM are the combined activation of multiple oncogenic pathways and intra-tumor heterogeneity. With multiple aberrant signaling pathways driving GBM, single target-single agent pharmacotherapies are likely to fail, even when using drugs that can penetrate the BBB. Consequently, we are exploring combinations of targeted agent that should cause concomitant inhibition of the common glioma associated oncogenic signaling pathways. Moreover, as radiotherapy is the cornerstone of the standard therapy, we are also actively investigating the options of radiosensitization by small molecule drugs. For this we closely collaborate with the research group of Gerben Borst. 

GBM is a highly complex disease that cannot be modelled with high-fidelity using in vitro models only. Consequently, we rely heavily on in vivo models for our research. We have developed and acquired a range of experimental mouse models of GBM that mimic many aspects of GBM in patients very closely. These include genetically engineered mouse models and human and murine transplantable glioma models. With our top-class animal facility housing 7T MRI, image-guided radiotherapy system and molecular and optical imaging modalities, we can make optimal use our state-of the-art models for interrogating the effects of experimental interventions. The impact of the drug transporters in the BBB is being studied by using transporter knockout mouse models. In collaborations with the research group of Jacco van Rheenen we are also implementing intravital imaging as a tool to visualize the response of intracranial tumors to therapies. With the help of these models, we try to uncover potentially exploitable vulnerabilities of gliomas in order to improve the prospects of patients that suffer from this devastating disease.

More about the Olaf van Tellingen group

Borst, Gerben

Gerben Borst

Division
Pharmacology
Specialisation

Introduction

In the preclinical setting our research group is focusing on optimizing the timing and duration of targeted agents in relation to the RT

These targeted agents involve the currently used radiosensitizers, and the more recently developed immunotherapy agents and agents targeting a specific factor that is involved in the radiotherapy response.

This research is executed in different models with the focus on glioblastoma patients. In addition we use also other models to uncover radiation escape and exploit new treatment strategies (e.g. breast cancer tumor models). It is our goal that with the knowledge of this preclinical research we can introduce novel treatment strategies in the clinic.   

In the clinical setting we study MRI based anatomical and functional characteristics and changes to guide our radiotherapy treatment delivery for patients with brain metastasis and glioblatoma. We also study the effect of changes on the dose coverage of the tumor to optimize the timing of the MRI and how to develop better radiotherapy treatment strategies to target this.

More about the Gerben Borst group

Share this page