Metabolic Modulation of Glioblastoma with Dichloroacetate
Science Translational Medicine
12 May 2010
Vol 2, Issue 31
p. 31ra34
Metabolic Modulators in Cancer
Cancer cells are optimized for growth, not performance. Their metabolism is geared to provide the raw materials needed for new cells, and that package includes resistance to apoptosis and mitochondria that run on aerobic glycolysis, not oxidative phosphorylation. In a small study, Michelakis et al. have taken advantage of these characteristics seen in glioblastoma, a deadly brain cancer, and examined the effects of a metabolic regulator, dichloroacetate, on tumor cells in culture and in patients, with some promising results.
Dichloroacetate activates pyruvate dehydrogenase, which in turn increases the flow of carbohydrates, in the form of pyruvate, into the mitochondria, where it enhances glucose oxidation by oxidative phosphorylation and decreases glycolysis. When the authors applied this agent to freshly excised glioblastoma tissue from 49 patients, the mitochondrial membrane potential (an index of mitochondrial function) improved, while it did not affect mitochondria from normal brain tissue. They then treated five glioblastoma patients with dichloroacetate, three of whom had recurring disease after traditional chemotherapy and two of whom were newly diagnosed. Three of the patients showed evidence of tumor regression on brain imaging scans, and four were clinically stable 15 months after therapy was initiated. Follow-up studies on cells taken from these patients before and after treatment showed that dichloroacetate normalized several mitochondrial functions, promoted apoptosis, and had other biochemical effects consistent with antitumor activity. Dichloroacetate appears to be safe to give to humans at doses that are required for pyruvate dehydrogenase inhibition. Now, this agent can be added to a growing group of metabolic modulators that may prove useful in cancer therapy.
Abstract
Solid tumors, including the aggressive primary brain cancer glioblastoma multiforme, develop resistance to cell death, in part as a result of a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis. This metabolic remodeling is accompanied by mitochondrial hyperpolarization. We tested whether the small-molecule and orphan drug dichloroacetate (DCA) can reverse this cancer-specific metabolic and mitochondrial remodeling in glioblastoma. Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by DCA. In a separate experiment with five patients who had glioblastoma, we prospectively secured baseline and serial tumor tissue, developed patient-specific cell lines of glioblastoma and putative glioblastoma stem cells (CD133+, nestin+ cells), and treated each patient with oral DCA for up to 15 months. DCA depolarized mitochondria, increased mitochondrial reactive oxygen species, and induced apoptosis in GBM cells, as well as in putative GBM stem cells, both in vitro and in vivo. DCA therapy also inhibited the hypoxia-inducible factor–1α, promoted p53 activation, and suppressed angiogenesis both in vivo and in vitro. The dose-limiting toxicity was a dose-dependent, reversible peripheral neuropathy, and there was no hematologic, hepatic, renal, or cardiac toxicity. Indications of clinical efficacy were present at a dose that did not cause peripheral neuropathy and at serum concentrations of DCA sufficient to inhibit the target enzyme of DCA, pyruvate dehydrogenase kinase II, which was highly expressed in all glioblastomas. Metabolic modulation may be a viable therapeutic approach in the treatment of glioblastoma.
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Supplementary Material
Summary
Materials and Methods
Results
Discussion
Fig. S1. Molecular characterization of GBM tumors.
Fig. S2. Evolution of tumor response in patient 1.
Fig. S3. Evolution of tumor response in patient 4.
Fig. S4. Evolution of tumor response in patient 5.
Fig. S5. GBM MRI from patient 3.
Fig. S6. Mitochondrial membrane potential in GBM-SC from freshly excised GBM tissue.
Fig. S7. Characterization of primary GBM cells and GBM-SC.
Fig. S8. HXKII in GBM cells derived from patients before and after chronic DCA treatment.
Fig. S9 Effects of DCA therapy on GBM-SC and vascular apoptosis.
Fig. S10. Effects of DCA on angiogenesis in vitro.
Fig. S11. Effects of DCA treatment on p53 and p21 activity in vivo.
Fig. S12. A proposed comprehensive mechanism for the anticancer effects of DCA in GBM (see Supplementary Discussion).
Table S1. Laboratory and clinical parameters of five GBM patients before and after DCA treatment.
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Published In
Science Translational Medicine
Volume 2 | Issue 31
May 2010
May 2010
Copyright
Copyright © 2010, American Association for the Advancement of Science.
Submission history
Received: 11 November 2009
Accepted: 23 April 2010
Acknowledgments
Funding: This study was funded by the Hecht Foundation (Vancouver, British Columbia, Canada; E.D.M.), the Canada Institutes for Health Research and the Canada Research Chairs Program (E.D.M.), and by public donations to the DCA program (received and managed by the Regents of the University of Alberta and the Faculty of Medicine). The authors would like to acknowledge the ort from the Alberta Health Services (D. Gordon, Senior Vice-President, Major Tertiary Hospitals). Author contributions: E.D.M. designed the studies, supervised the mechanistic studies, secured the funding, analyzed the data, and wrote the manuscript. K.C.P. co-designed the studies, supervised all clinical studies, and co-wrote the manuscript. G.S. and P.D. performed all the mechanistic studies and edited the manuscript. L.W. coordinated all studies, contributed to data acquisition, analyzed the clinical data, and edited the manuscript. A.H., E.N., C.M., T.-L.G., and M.S.M. contributed to data acquisition and data analysis and edited the manuscript. J.R.M., D.F., and B.A. co-designed the clinical studies, contributed to data acquisition, and edited the manuscript. Competing interests: E.D.M. is the co-owner of a pending use patent on the use of DCA as a cancer therapy. There has been no active or planned commercialization of this patent.
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