Background

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.

Technology Overview

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.

Figure 1: DCA Induces GBS Tumour Regression.

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.

Figure 2: DCA is Synergistic with Temodar and Induces Apoptosis in GBS Stem Cells.

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.

Further Details

Small clinical trial was published in 2010 in GBS patients: Michelakis, ED et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med. 2010 May 12;2(31).

State of Development

Clinical development

Benefits

Positive survival signal in small clinical study
Specifically targets tumour tissue by mechanism of action (Inhibition of Warburg Effect)
Induces apoptosis in tumour cancer stem cells (CD 133+, nestin+) – source of drug resistance, cause of GBS cancer recurrence and ultimately death
In vivo validation of mechanism of action of DCA
Synergistic with existing gold standard drug (Temodar (temozolomide))

Applications

Glioblastoma – both adult and paediatric and other cancers (lung plus others)

Potential Markets

GBS is an Orphan Drug patient population in US and EU – data exclusivity for 7 and 10 years respectively

Opportunity

Available for exclusive licensing

Novel Treatment for Glioblastoma

Patents

IP Status

Seeking