Thesis
Novel repurposed drug combinations for the treatment of glioblastoma
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2025
- Thesis identifier
- T17324
- Person Identifier (Local)
- 201961529
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Glioblastoma is the most aggressive and malignant subtype of brain and central nervous system cancers, accounting for >50% of all gliomas in adults. The glial tissue tumours cause over 1% of all cancer related deaths with the 5-year relative survival being 5% and 10-year survival rates being as low as 2%. Current treatments for the disease include, surgery, radiotherapy and the chemotherapy Temozolomide (TMZ), however in many cases the treatments fail due to a build-up of resistance to treatment causing aggressive recurrences. With increasing resistance in patients, the need for new novel treatment approaches is needed which minimise the burden of the disease on patients as well as the side effects. Monomethyl Fumarate (MMF) is a direct metabolite of Dimethyl Fumarate (DMF), a fumaric acid, currently used for the treatment of MS and psoriasis. Similarly to DMF, MMF has an inhibitory effect on the NrF2 pathway regulating the antioxidant glutathione. We hypothesised that the inhibitory effects on glutathione are time-dependent and after 24 hours of treatment, MMF becomes an NrF2 stabiliser, restoring its neuroprotective role against reactive oxygen species. Therefore, scheduling combinations of MMF with TMZ and radiotherapy would increase the treatment combinations efficacy by utilising the time window where glutathione levels have dropped to get the maximum response from the treatment combination. We have shown in three glioblastoma cell lines, U87, UVW and T98g that the combination of MMF with TMZ is synergistic in all cell lines, regardless of the cell DNA repair protein, MGMT status, when the combinations are scheduled. We also found the simultaneous combination to be synergistic when given simultaneously in the MGMT positive cell line T98g. Scheduling was assessed through glutathione detection over a range of time points. From our studies we have found the combination and MMF alone to initiate initial DNA damage, via comet assay. Triple combination studies of MMF, TMZ and RT also showed synergistic activity at both 1Gy and 2Gy doses. Glutathione assays, RT-qPCR and Ferroptosis assays were performed to distinguish differences between the fumarates and elucidated to a time and dose responsive effect of MMF and DMF on the cell lines. Differences in the GBM response to DMF and MMF were suggestive of an iron dependent, ferroptosis cell death pathway. However, future work is needed before development of MMF as a clinically relevant GBM therapeutic.
- Advisor / supervisor
- Mullen, Alexander
- Boyd, Marie
- Resource Type
- DOI
Relations
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PDF of Thesis T17324 | 2025-06-03 | Public | Download |