High grade gliomas (WHO grade III and IV)(HGG) are the most common malignant, and aggressive
brain tumour in humans. Current understanding of the mechanisms contributing to their growth
and progression remain limited. Furthermore, treatment options have not advanced in recent
decades. Recently, it has become evident that these tumours are dependent on glucose
metabolism to maintain oncogenic properties. From a preclinical standpoint, targeting
hexokinase 2 (HK2), the first committed step of glucose metabolism, with azole class drugs
has been shown to display favourable anti-tumour effects in both in vitro and in vivo HGG
models. We would like to translate these preclinical findings into the clinical setting by
implementing a proof-of biological concept study with two azole drugs: ketoconazole (KCZ) and
posaconazole (PCZ). A small cohort of recurrent HGG patients will receive either a single-,
or repeated, steady state dose of either KCZ or PCZ and will then go for surgery where drug
concentrations will be measured intraoperatively. Study drug selection and dosing details
will be selected based on urgency of surgery and patient clinical characteristics Downstream
biological effects of drug on tumour tissue, including HK2 activity, will also be assessed.
This study will provide a preliminary understanding of azole drug activity in recurrent HGG
patients and will help inform future studies of azole drug efficacy in this patient
population