Glioblastoma cells creep along fluid-filled channels in the brain to spread, and a new project aims to block those routes while simultaneously improving how cancer-killing immune cells reach the tumour. This matters because glioblastoma—the most aggressive form of brain cancer—almost always returns after treatment. The tumour cells infiltrate healthy tissue by migrating through perivascular spaces, the same narrow pathways the brain’s recently discovered glymphatic system uses to flush out waste. The researchers will test whether drugs that modulate a water-channel protein called aquaporin-4 can slow tumour invasion and, separately, whether delivering CAR T-cells directly into cerebrospinal fluid improves their access to the tumour. A next-generation imaging technique called photoacoustic imaging will, for the first time, allow the team to watch both tumour cells and immune cells moving inside the living brain at high resolution. If the approach works, it could fundamentally change how brain tumours are treated—not by attacking the cancer directly, but by manipulating the physical environment through which it spreads. The project is primarily fundamental science, exploring a biological mechanism that has never been visualised in action. A deeper understanding of glymphatic clearance in cancer could eventually lead to entirely new classes of therapy that combine physical barrier disruption with cellular immunotherapy.
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This is a unique multidisciplinary collaboration between CAR T-cell biologists Martin Pule and Karin Straathof, imaging biophysicist Mark Lythgoe, and neuroscientist Ian Harrison to visualise the effects of modulating brain clearance on both cancer progression and CAR T-cell therapy. Glioblastoma (GBM), an aggressive brain tumour, features diffuse infiltration of the cells into the surrounding tissue, conferring treatment resistance and leading to inevitable recurrence. GBM tumour cells invade along pre-existing brain structures, where migration occurs through the perivascular space. The glymphatic system is a newly discovered brain-wide clearance system that uses perivascular spaces, formed by astrocytic endfeet, to promote elimination of waste from the brain. Aquaporin-4 (AQP4) channels polarized to astrocytic endfeet are integral for glymphatic function and brain water transport. This system can be pharmacologically modulated by targeting this water channel with small molecules; we have shown that glymphatic function can be both up and down regulated with AQP4 facilitator/inhibitor compounds respectively, highlighting its therapeutic potential. We aim to investigate the role of AQP4 in tumour cell movement through the perivascular space potentially unveiling a new target for therapy. Insufficient trafficking of CAR T-cells to tumour sites has impeded the success of this therapy in solid tumours, including GBM. Recent studies have shown that administering CAR T-cells directly into the CSF is more potent compared to intravenous administration, while attenuating off-target effects. As such, we will investigate the effects of modulating CSF glymphatic clearance on T-cell ingress, which will improve our understanding of the access of CAR T-cells to brain tumour, in order to improve treatment protocols. Visualizing cells in vivo within the deep brain has not been possible previously. This will be achieved by employing photoacoustic imaging (PAI), a next-generation cell imaging technology which will permit high-resolution in vivo imaging of multiple cell types and facilitate the investigation of the role of the glymphatic system in tumour invasion and penetration of CAR T-cells into parenchymal CNS tissue. Understanding this key phenomenon in brain cancer biology may potentially revolutionize therapeutic approaches, promising vital benefits for brain tumour patients.
Discovery Research Committee - Multidisciplinary Project
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