Glioblastoma Treatment

About

Glioblastoma (GBS) is the most common form of a malignant brain tumour as well as the most aggressive. GBS remains one of the most lethal cancers with median survival ~15 months and two-year survival is 30% even with gold standard Temodar (temozolomide) treatment. 5-year survival rate is less than 10%. Standard of care is de-bulking surgery, followed by radiation and chemotherapy with Temodar. The incidence of GBS is ~15,000 in US and 13,000 in EU. Avastin was approved for treatment of glioblastoma after small single arm Phase II trials and despite no improvement overall survival. 60% and 80% of patients fail first and second-line therapies with Temodar and Avastin, respectively. Improved treatments remain a large unmet need. Many cancer cells express a biological mechanism called the Warburg Effect. Essentially this is the use of cytosolic glycolysis for production of cellular energy and is anaerobic. It is preferred even in the presence of oxygen by tumour cells. This has been demonstrated for human GBS tumour cells in GBS patients by 18F-fluorodeoxyglucose (FDG) PET imaging – and verified in GBS cell cultures. Dichloroacetate (DCA) prevents cancer cells from using glycolysis (i.e. prevents Warburg Effect) by inhibiting pyruvate dehydrogenase kinase (PDK). This activates pyruvate dehydrogenase and stimulates the need to use oxidative phosphorylation to produce cellular energy. The end result is enabling the mitochondria to induce apoptosis (cell death) of the malignant cells via decreased activation of proproliferative transcription factors (like NFAT and HIF1α) and increasing the activity of Kv channels and the tumour suppressor protein p53. The benefits of DCA were seen on fresh tissue from 49 GBM patients where mitochondrial membrane potential (an index of Warburg effect (mitochondrial function)) improved while having no effect on normal tissues. Clinical investigation on 5 GBM patients (3 recurring after standard chemo; 2 newly diagnosed) with DCA resulted in 3 pts having tumour regression (found by imaging) with 4 having stabilized disease 15 months after treatment start (i.e. beyond predicted median survival time). Evaluation of tumour tissues pre/post DCA treatment found DCA normalized several mitochondrial functions, promoted apoptosis, and had other biochemical effects consistent with anti-tumour activity.