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Cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, failed to show benefit over lomustine in relapsed glioblastoma. One resistance mechanism for cediranib is up-regulation of epidermal growth factor receptor (EGFR). This study aimed to determine if dual therapy with cediranib and the oral EGFR inhibitor gefitinib improved outcome in recurrent glioblastoma. This was a multi-center randomized, two-armed, double-blinded phase II study comparing cediranib plus gefitinib versus cediranib plus placebo in subjects with first relapse/first progression of glioblastoma following surgery and chemoradiotherapy. The primary outcome measure was progression free survival (PFS). Secondary outcome measures included overall survival (OS) and radiologic response rate. Recruitment was terminated early following suspension of the cediranib program. 38 subjects (112 planned) were enrolled with 19 subjects in each treatment arm. Median PFS with cediranib plus gefitinib was 3.6 months compared to 2.8 months for cediranib plus placebo (HR; 0.72, 90% CI; 0.41 to 1.26). Median OS was 7.2 months with cediranib plus gefitinib and 5.5 months with cediranib plus placebo (HR; 0.68, 90% CI; 0.39 to 1.19). Eight subjects (42%) had a partial response in the cediranib plus gefitinib arm versus five patients (26%) in the cediranib plus placebo arm. Cediranib and gefitinib in combination is tolerated in patients with glioblastoma. Incomplete recruitment led to the study being underpowered. However, a trend towards improved survival and response rates with the addition of gefitinib to cediranib was observed. Further studies of the combination incorporating EGFR and VEGF inhibition are warranted. ClinicalTrials.gov NCT01310855.

Glioblastoma multiforme is associated with poor prognosis and resistance to standard therapy. However the non-dividing nature of normal brain provides an opportunity for enhancing the therapeutic ratio by combining radiation with inhibitors of replication-specific DNA repair pathways. KU-0059436, an inhibitor of the base excision repair (BER) protein poly(ADP-ribose) polymerase (PARP), was demonstrated to specifically radiosensitise glioma cells during S-phase and to increase lonising radiation (IR)-induced γH2AX and Rad51 foci. This radiosensitisation was enhanced using fractionated radiation, possibly because more cells were exposed to IR whilst in S-phase. A model is proposed whereby PARP inhibition decreases repair of radiation-induced single strand breaks (SSB) which are converted at collapsed replication forks to double strand breaks (DSB) requiring homologous recombination (HR) for repair. To investigate whether inhibition of downstream HR repair potentiates the radiosensitising effect of KU-0059436, and in the absence of specific HR inhibitors, the heat shock protein 90 (HSP90) inhibitor 17-AAG was used. This compound exhibits tumour-specific cytotoxic and radiosensitising properties and downregulates the HR proteins BRCA2 and Rad5l. Work in this thesis confirmed that 17-AAG inhibits HRR and radiosensitises glioma cells. Radiosensitisation was replication-dependent and was increased in the presence of KU-0059436. The combined effect was at least partially replication-dependent, was associated with increased γH2AX foci in G2 cells, and was absent in non-malignant CHO cells. Since Rad5l-depleted cells were also radiosensitised by 17-AAG, this effect could not be attributed entirely to HRR inhibition. 17-AAG inhibits multiple tumour survival and DNA repair pathways that may contribute to its enhancement of the replication-dependent effects of KU-0059436. These multiple mechanisms may be difficult to elucidate but are likely to be therapeutically beneficial. In summary, the combination of HSP90 and PARP inhibitors may potentially improve brain tumour radiotherapy by mechanisms that include but are not restricted to inhibition of the BER and HRR DNA repair pathways.