5B. Crossing barriers with multi-drug therapy in high-grade brain tumours

H3K27M-altered diffuse midline glioma (DMG) is a deadly brain cancer that mostly occurs in children and young adults. Despite decades of clinical trials, survival has remained largely unchanged. Resistance to treatment is multifactorial. Intrinsic tumour cell resistance, as well as subclonal spatial and temporal heterogeneity can explain part of the ineffectiveness of previous treatments. These tumours furthermore display an intact blood-brain barrier which prevents more than 90% of drugs from entering the tumour to therapeutic concentrations.

Focused ultrasound-mediated BBB opening (FUS-BBBO) is a technology with which the BBB can be temporarily and locally opened using microbubbles injected into the bloodstream. These microbubbles are subsequently induced to oscillate in the blood vessels of the brain with ultrasound delivered non-invasively outside the skull. This causes temporary and local disruption of the tight junctions of the endothelial cells in the BBB, as well as stimulation of transcytosis. Convection-enhanced delivery (CED) is another drug delivery technique that allows for delivery of therapeutics to the brain using a constant pressure flow over mini-catheters placed into the tumour and its (immune) micro-environment.

The introduction of these abovementioned drug delivery technologies literally opens up an infinite number of possibilities to introduce new or repurpose previously discarded drugs into the treatment of DMG. Research into the pharmacokinetic (PK) needs for effective delivery with these techniques, however, is largely lacking.

This project will focus in vitro on PK profiles on chip that mimic drug concentrations in patients, both in plasma as in brain tissues. In PDX and GEMM models of DMG, these PK profiles will be mimicked as much as possible using osmotic pump systems in combination with these drug delivery technologies. The findings from this research will better predict which schedules should be used in clinical trials using FUS-BBBO or CED in patients suffering from these detrimental cancers.