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Abstract
Glioblastoma (GBM) is a highly aggressive primary brain tumour occurring in adults and children. The current standard treatment is maximal tumour resection followed by radiotherapy with concurrent and adjuvant temozolomide (TMZ) chemotherapy. Currently, median survival remains at approximately 15 months and less than 5% of patients survive longer than 5 years. Patients harbouring methylation within the MGMT promoter hold a survival advantage. Unfortunately, the majority of GBM patients (~60%) do not harbour a methylated MGMT promoter and treatment options available for these patients are very limited. Hence, there is an urgent need to develop novel therapeutic approaches focused on this subset of patients.
The overarching aim of this thesis is to undertake a personalised therapeutic approach through precision medicine by identifying targetable molecular markers within a patient’s whole genomic profile. A patient-derived model (G89), for both in vitro and in vivo investigations, was developed and characterised. Three molecular targets were identified using a commercial biotargeting system and in-house whole genome sequencing. These targets were topoisomerase I, mammalian target of rapamycin (mTOR) and poly ADP ribose polymerase (PARP). Inhibition of these targets were
investigated in vitro and in vivo on G89 along with other GBM patient-derived models. In addition, mTOR and PARP inhibition was investigated in vitro and in vivo in combination with an organo-arsenic mitochondrial inhibitor (PENAO) and radiotherapy, respectively. Variable responses were observed. Treatment with topoisomerase inhibitors elicited poor response. Promising responses with the combination of a mTOR inhibitor with the mitochondrial inhibitor, PENAO, were observed in vitro (p < 0.05) but did not show appreciable effects in vivo. PARP inhibition in combination with radiotherapy, on the other hand, showed remarkable response both in vitro (p < 0.001) and in vivo (Log-rank p value = 0.042).
Overall, the attempt to carry out a personalised treatment approach led us to identify and develop novel therapeutic combinations. The findings of this thesis have led to a successful novel therapeutic combination for GBM patients with unmethylated MGMT promoter that is currently being tested in a clinical trial.