EditorialBrain Cancer

Targeting Cell Metabolism in Cancer Patients

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Science Translational Medicine  12 May 2010:
Vol. 2, Issue 31, pp. 31ed1
DOI: 10.1126/scitranslmed.3001210
CREDIT: C. DRONSFIELD

In this issue of Science Translational Medicine, Michelakis et al. report the first use of dichloroacetate (DCA) to treat cancer in humans (1). DCA was administered to five patients with glioblastoma, an aggressive primary brain cancer with limited therapeutic options. The results of the study showed that DCA could be given safely to patients at a dose capable of altering tumor cell metabolism in vivo. Although the study was not designed to determine clinical efficacy, it suggests that therapies aimed to target tumor metabolism might be beneficial to cancer patients.

Tumor cell metabolism is different from that of most normal cells (2). Cancer cells metabolize glucose primarily by aerobic glycolysis. Relative to normal cells, many tumors exhibit increased glucose uptake and metabolism, which result in enhanced lactate production (called the Warburg effect). DCA has been used to treat acidosis from excess lactate accumulation in noncancer patients with rare inborn errors of mitochondrial metabolism (1). DCA reduces lactate production by inhibiting pyruvate dehydrogenase kinase (PDK) (3), a negative regulator of the mitochondrial pyruvate dehydrogenase complex (PDH). PDH catalyzes the oxidative decarboxylation of pyruvate to acetyl–coenzyme A, allowing its entry into the tricarboxylic acid cycle and away from lactate production. Thus, Michelakis et al. hypothesized that DCA could be used to inhibit the metabolism of glucose to lactate in cancer cells and that this inhibition of aerobic glycolysis might be beneficial for cancer therapy. The study was not designed to determine whether DCA provides a clinical benefit to glioblastoma patients, but three of the five patients demonstrated a better than expected response to therapy, and four of the patients remained alive for at least 18 months after starting therapy.

Previous efforts in humans to target altered cancer cell metabolism using glucose analogs have not been successful in part because of unacceptable toxicity (4). In this study, all patients tolerated prolonged exposure to a dose of 6.25 mg per kilogram of body weight, with no reported side effects (1). At this dose, the plasma concentration of DCA remained above that needed to inhibit PDK in vitro (1). Importantly, the authors showed that when PDH activity was measured in tumor samples from patients receiving DCA, the activity was higher than that observed in tumor tissue resected from the same patient before starting DCA. This demonstrates that DCA therapy can cause increased PDH activity in the tumor. Taking advantage of the tumor samples obtained from patients before and after starting DCA, Michelakis and colleagues demonstrated that DCA can also alter mitochondrial membrane potential and increase reactive oxygen species production in tumor cells. Thus, this study illustrates the value of incorporating tissue biopsies into clinical trials before and after starting therapy. If used more broadly, this approach will improve our understanding of how compounds function at the sites of the tumors in patients and help to develop more effective uses of these therapies.

The exact mechanism(s) by which DCA alters mitochondrial physiology and how these alterations influence tumor cell metabolism, growth, and survival remain unclear. The authors hypothesize that DCA kills cancer stem cells and prevents angiogenesis to exert an antitumor effect (1). Regardless of whether or not this hypothesis proves to be correct, it appears that DCA activates PDH and alters cancer cell metabolism in patients. Normal cells also rely on glucose metabolism, and questions have been raised about whether a sufficient therapeutic window exists to target enzymes that are central to normal metabolic pathways (2). These results suggest that such drugs can disrupt the metabolism of tumor cells and be administered safely to patients. Time will tell whether this strategy constitutes an effective cancer therapy.

Footnotes

  • Citation M. G. Vander Heiden, Targeting cell metabolism in cancer patients. Sci. Transl. Med. 2, 31ed1 (2010).

References

  1. The author is a consultant and scientific advisory board member for Agios Pharmaceuticals.

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