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Treatment of brain tumors

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. 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.

 

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