Focused Ultrasound-mediated Blood-Brain Barrier Opening for Diffuse Midline Glioma Radiosensitisation

Abstract

Diffuse midline glioma (DMG), previously known as diffuse intrinsic pontine glioma when located in the pontine area, is a very aggressive paediatric brain tumour. After diagnosis, children with pontine DMG have a poor prognosis with a median survival of 11 months and a mortality rate of 95% within two years. Due to the location and invasive growth of the tumour, is DMG difficult to treat. Surgery is practically impossible, chemotherapy is limited due to the blood-brain barrier (BBB) and radiotherapy, which it is still the current treatment option, is restricted by severe side-effects and radio resistance occurrence. Microbubble and focused ultrasound-mediated BBB opening (FUS-BBBO) has made drug delivery into the brain parenchyma and potentially the tumour possible. Drug delivery of radiosensitisers, compounds that render tumour cells sensitive to radiation, by FUS-BBBO in combination with radiotherapy can have a beneficial effect for the patients. Although radiosensitization seems be a promising method for the treatment of DMG, there is no conclusive evidence regarding its effectiveness. The goal of this thesis was to validate the treatment effectiveness of radiosensitization through FUS-BBBO-mediated drug delivery in a DMG patient-derived xenograft (PDX) mouse model.