Examining negative modulators of glutamatergic receptors as anti-cancer agents in glioblastomas

Spagnolello, Julia 2025. Examining negative modulators of glutamatergic receptors as anti-cancer agents in glioblastomas. MPhil Thesis, Cardiff University. Item availability restricted.

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Abstract

Glioblastoma (GBM) is an aggressive brain tumour, representing approximately 50% of all primary brain malignancies. The median survival for GBM patients is 20 months, with less than 10% surviving beyond 5 years post-diagnosis. Currently, there are no FDA-approved targeted therapies for GBM. Recent studies have highlighted the crucial role of glutamate signalling in GBM tumour growth and migration, with functional neurogliomal synapses forming and firing glutamate between neurons and GBM cells. Moreover, preliminary data show that glutamatergic antagonists inhibit tumour progression. Therefore, this study investigates the potential of glutamatergic receptor modulators as novel therapeutic agents for GBM. Using patient-derived GBM cell lines (U3042, U3019 and L2) we identified the ionotropic glutamate receptors and their subunit compositions that are overexpressed in GBM. Here, qPCR and western blot analyses revealed that AMPA receptors were the most highly expressed, followed by Kainate and NMDA receptors, with U3042 exhibiting the highest levels of expression. Notably, GRIA2, GRIA3, and GRIK3 subunits were found to be particularly enriched in GBM cells compared to normal human astrocytes. To then assess the proliferative effects of glutamate, cell proliferation was measured using cell-titre glow and Ki-67 staining assays. Here, U3042 cells exhibited a significant proliferative response to 500 µM glutamate, while U3019 cells did not. Interestingly, in this study treatment with glutamatergic antagonists did not reduce proliferation in these cell lines. Additionally, the impact of glutamate on intracellular calcium fluctuations was explored. Here, glutamate at 500 µM significantly enhanced calcium signalling, with similar effects observed using s-AMPA and kainic acid, two glutamatergic specific compounds. Lastly, the addition of Perampanel and UBP-302, two glutamatergic antagonists targeting AMPA and Kainate respectively, significantly decreased these calcium fluctuations. These results suggest that glutamate, via the AMPA and Kainate receptor subunits, may promote GBM cell proliferation through the influx of intracellular calcium. Therefore, targeting these glutamatergic pathways with negative modulators holds promise as a novel therapeutic strategy for treating GBM.

Item Type:	Thesis (MPhil)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	11 July 2025
Date of Acceptance:	11 July 2025
Last Modified:	14 Jul 2025 09:33
URI:	https://orca.cardiff.ac.uk/id/eprint/179736

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