Glioblastoma is one of the most aggressive primary brain tumours in adults, with a median overall survival of just over a year after diagnosis. Although treatment with temozolomide (TMZ)— the current standard chemotherapy— is effective, more than 50% of tumours are resistant to this agent as a consequence of the overexpression of methylguanine methyltransferase (MGMT), which repairs TMZ-induced cytotoxic DNA damage. The small nucleoside inhibitor O6-benzylguanine (O6BG) can bind to MGMT and deplete its activity, therefore restoring TMZ sensitivity. However, administration of O6BG causes myelosuppression, rendering this treatment toxic and difficult to tolerate. Adair et al. have carried out a prospective clinical trial to test whether gene therapy can prevent haematopoietic toxicity and promote tolerance and efficacy of the combination regimen with O6BG and TMZ.
The authors also used a patient-specific mathematical model of tumour growth to determine the potential benefits achieved with the addition of O6BG to TMZ therapy, using data from patients treated with standard care regimens as controls. They examined two magnetic resonance imaging (MRI) scans — at presentation and before surgical resection — and used this mathematical model to predict the growth of the tumours, had they been left untreated. The mathematical model showed a marked delay in predicted tumour growth in tumours treated with lower cumulative doses of TMZ when administered with O6BG.
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