Metabolic Modulation of Glioblastoma With Dichloroacetate

Metabolic Modulation of Glioblastoma With Dichloroacetate

Glioblastoma is an aggressive brain tumor characterized by altered cellular metabolism, often relying heavily on glycolysis rather than mitochondrial oxidative metabolism. Michelakis and colleagues investigated whether dichloroacetate (DCA), a small molecule known to influence mitochondrial metabolism, could modify this metabolic pattern and affect tumor growth in patients with glioblastoma.
The study combined laboratory research with a small clinical component involving patients with recurrent glioblastoma who received oral DCA. Researchers examined tumor metabolism, mitochondrial function, and markers of cell death in tumor tissue, while also monitoring clinical safety and preliminary signals of therapeutic activity. Laboratory experiments using glioblastoma cells showed that DCA inhibited pyruvate dehydrogenase kinase, leading to increased mitochondrial activity, reduced glycolysis, and activation of pathways associated with apoptosis.
In tumor samples and imaging studies, DCA appeared to reverse some of the metabolic abnormalities characteristic of glioblastoma. The treatment was associated with increased mitochondrial function, changes in markers related to tumor metabolism, and evidence of increased tumor cell apoptosis in laboratory models. In the small group of treated patients, DCA was generally well tolerated, and some individuals demonstrated radiographic or metabolic changes suggesting potential biological activity.
Although the clinical component involved only a small number of patients and was not designed to determine treatment efficacy, the study provided an important proof-of-concept that targeting cancer metabolism may influence glioblastoma biology. These findings support further investigation of metabolic therapies such as DCA in larger clinical trials to determine whether metabolic modulation can improve outcomes for patients with glioblastoma.

Reference:

Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS, Petruk KC. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med. 2010;2(31):31ra34. doi:10.1126/scitranslmed.3000677. PMID: 20463368.