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Abstract
High grade gliomas (HGG) are the most common primary brain tumour in adults. Radiation therapy has a key role in the management of HGG. The aims of this thesis are to document and improve the radiotherapy outcomes in this disease. This is achieved by 1) Utilising the AGOG (Australian Genomics and Clinical Outcomes of Glioma) database of patients from seven major tertiary hospitals to document the pathological, surgical, radio- and chemotherapeutic patterns of care in Australia; 2) Using non-invasive imaging biomarkers such as the oscillating gradient spin echo (OGSE) MRI to monitor radiotherapy response; 3) Enhancing the effect of radiation therapy by using the glycolytic inhibitor dichloroacetate.
By analysing the AGOG database, the treatment outcomes achieved in Australia are comparable to that in published randomised trials. The radiotherapy utilisation rate is very high and systemic therapy is in line with many international published series. However, several areas of potential improvement have been identified and include the reduction in prophylactic anti-epileptic use and increase in clinical trial enrolments.
The efficacy of radiation therapy is often not known until well after all the therapy has been delivered and the patient returns for progress imaging. Using a novel MRI OGSE, which measures the apparent diffusion coefficient (ADC) over short diffusion distances, better visualisation of the brain tumour can be achieved and the tumour response can be assessed much earlier and reliably than conventional DWI (diffusion weighted imaging) methods. This offers the potential to modify therapy during the course of treatment or use dose painting techniques to dose escalate non-responding regions.
Up-regulated glycolysis is associated with radiation resistance. Elevated glycolysis in GBM (Glioblastoma) cells was observed post-RT together with up-regulated hypoxia inducible factor (HIF)-1α and its target pyruvate dehydrogenase kinase 1 (PDK1). Dichloroacetate (DCA), a PDK inhibitor currently being used to treat lactic acidosis, can modify tumour metabolism by activating mitochondrial activity to force glycolytic tumour cells into oxidative phosphorylation. DCA alone demonstrated modest anti-tumour effects in both in vitro and in vivo models of GBM and has the ability to reverse the RT-induced glycolytic shift when given in combination. In vitro, an enhanced inhibition of clonogenicity of a panel of GBM cells was observed when DCA was combined with RT. Further mechanistic investigation revealed that DCA sensitised GBM cells to RT by inducing the cell cycle arrest at the G2/M phase, reducing mitochondrial reserve capacity, and increasing the oxidative stress as well as DNA damage in GBM cells together with RT. In vivo, the combined treatment of DCA and RT improved the survival of orthotopic GBM-bearing mice.
In conclusion, several avenues have been identified which may lead to improved outcomes for patients with HGG. This includes reducing prophylactic anti-epileptic use and increasing clinical trial participation. There is also potential to develop OGSE sequences for human scanning as an early non-invasive marker of treatment response. Dichloroacetate combined with radiation therapy also warrants further study in pre-clinical studies and clinical trials.