Glioblastoma multiforme is an invariably terminal cancer, with 5-year survival rates as low as 1.9% in some patient groups. The current treatment for glioblastoma is surgery, external beam radiotherapy and adjuvant and concomitant temozolomide chemotherapy. Treatment will fail due to an inherent treatment resistance, and as aresult, current treatment for glioblastoma has been designated as an unmet clinical need, meaning that new and more efficacious treatment options are needed. Dimethyl fumarate is a clinically available immunomodulatory drug, currently used to treat multiple sclerosis.One of the targets of dimethyl fumarate is glutathione, a potent chemo- and radio-resistance factor. We hypothesised that the use of dimethyl fumarate as an adjuvant to standard of care chemo-radiotherapy would increase the efficacy of treatment via glutathione inhibition and subsequent amplification of chemo-radiotherapy effects on a molecular level. We have shown, using bespoke combinations of temozolomide and dimethyl fumarate in two glioblastoma cell lines, that our hypothesis was correct. Cell line specific combinations of temozolomide and dimethyl fumarate significantly increased cell kill in a dose dependent manner.Unfortunately, a precise mechanism for this combination was unable to be elucidated. There was no significant increase in DNA double strand breaks, cell cycle arrest or apoptotic induction when temozolomide treatment and X-irradiation was combined with dimethyl fumarate. We were able to positively identify glutathione as a chemoresistance factor in these cell lines, as well as rule out the role of reactive oxygen species. We have also shown however, that dimethyl fumarate is capable of activating the chemo- and radioresistance factorNRF2. We believe that this is the first mechanistic interrogation of dimethyl fumarate being used to potentiate combined chemo-radiotherapy, however future work is needed before potential clinical deployment of dimethyl fumarate as an anti-neoplastic agent.
|Date of Award||23 Mar 2020|
- University Of Strathclyde
|Sponsors||University of Strathclyde|
|Supervisor||Alexander Mullen (Supervisor) & Marie Boyd (Supervisor)|