On Wednesday April 15th, 2009 Nienke de Vries will defend her thesis titled “Preclinical models to study the impact of the blood-brain barrier in brain tumor chemotherapy” in order to obtain the doctorate degree from the University of Utrecht. Her promoter is professor Jos Beijnen, her co-promotor is dr. Olaf van Tellingen
High-grade gliomas, in particular Glioblastoma Multiforme (GBM), are the most common primary brain tumors in adults and among the deadliest of human cancers. Their location and the extensively infiltrative character of tumor cells into surrounding normal brain structures is an impediment for all therapeutic interventions. The blood-brain barrier (BBB) is of pivotal importance to maintain homeostasis of the central nervous system (CNS), but unfortunately also evade transport of many chemotherapeutic drugs, making this disease refractory to most chemotherapy regimens. Inadequate drug entry into the brain is partly mediated by drug efflux transporters localized in the BBB, which transport virtually all drugs back into the bloodstream. Besides the well described drug efflux transporter P-glycoprotein (P-gp, MDR1, ABCB1), this thesis demonstrates the important role of the more recently identified drug efflux transporter Breast Cancer Resistance Protein (BCRP, ABCG2), as another gate-keeper next to P-gp in the BBB by using drug transporter knockout mice. Absence or inhibition of both P-gp and BCRP (P-gp-/-Bcrp-/- knockout mice) resulted in increased brain penetration of cytotoxic and molecular-targeted anticancer agents. Importantly, the improved brain penetration of temozolomide translated into a significantly better antitumor response in an experimental intracranial tumor model.
The majority of preclinical studies are performed in xenografts, in which established mouse and human glioma derived cell lines are implanted into the flank or brain of immunodeficient mice. Although these models are standardized and generate reproducible tumors, they do not appropriate recapitulate many of the features that characterize high-grade gliomas and have therefore been less predictive of human response to drugs. Nienke therefore generated a new high-grade glioma model based on defined genetic alterations that result in spontaneous tumor formation in a more or less normal microenvironment in immunocompetent mice, and which resemble many features of the human disease. Furthermore, tumor inducement and response can be visualized non-invasively using bioluminescence imaging, thereby making this model more suitable for intervention studies.
Studies described in this thesis clearly underline that Bcrp1 and P-gp are two dominant drug transporters at the BBB that work in concert in limiting the brain penetration of several agents. Consequently, these results provide a solid base for further clinical testing of combinations of anticancer agents with drug transporter inhibitors in patients suffering from malignant glioma. The new high-grade glioma mouse model described in this thesis may have potential applicability for preclinical testing of new therapies against malignant gliomas.
The thesis defence is open to the public and will take place in the Academiegebouw, Utrecht, at 14.30 hours.