A novel approach to reverse Warburg metabolism in patients with recurrent glioblastoma: A phase II pharmacodynamic study of dichloroacetate

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ID: 326386
2026
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Abstract
Abstract Background Glioblastomas are characterized by the Warburg effect, driven by upregulation of pyruvate dehydrogenase kinase (PDK), which inhibits pyruvate dehydrogenase complex (PDC), leading to lactate accumulation. Dichloroacetate (DCA) is a potent and safe PDK inhibitor that crosses the blood-brain barrier, reverses Warburg metabolism, and reduces lactate levels. Methods This trial (RO1FD007271) evaluated the pharmacodynamics and pharmacokinetics of oral DCA in recurrent glioblastoma patients requiring surgical debulking. The primary endpoint was decreased PDC phosphorylation (p-PDHA1) in resected tumors. Patients received either one week of DCA or no DCA prior to surgery. All patients received DCA post-operatively. Enhancing and non-enhancing tumor tissue, and serial plasma DCA and lactate levels were analyzed. Results 37 patients were enrolled (median age=60 years). In DCA-treated patients, the contrast-enhancing tumor had lower p-PDHA1, PDK4, HIF1-α, VEGF-α, and PGK1 expression (all p < 0.05) than non-DCA treated patients. In non-enhancing tumors, p-PDHA1 and PDK 1-3 expression were not different, but PDK4, PCNA and PGK1 levels were reduced, and ERK1/2 was increased in DCA-treated patients (all p ≤ 0.01). At surgery, DCA-treated patients had lower plasma lactate (p = 0.004) than untreated patients. Post-operatively when all patients received DCA, plasma lactate fell dramatically (p < 0.001). DCA was well-tolerated but did not delay tumor recurrence. Conclusions In recurrent glioblastomas, DCA was safe, well-tolerated, and promoted aerobic respiration. It reduced markers of tumor cell proliferation and lowered plasma lactate. Although no clinical benefit was noted, further studies of combination therapy are indicated, given the known association between poor cancer outcomes and elevated PDK expression and lactate levels.
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Authors Carolyn O. Dirain, Stuart A. Grossman, Xiaobu Ye, Priya Sambasivan, Puranjay Shori, Himashi Liyanarachchi, Thomas D Franklin, Joy Fisher, Trisha Surakus, Michaella Iacoboni, Matthias Holdhoff, Karisa C. Schreck, Stephen B. Tatter, Richard E. Wagner, Roy Strowd, Chetan Bettegowda, Peter W. Stacpoole
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Journal Neuro-Oncology Advances
Year 2026
DOI
10.1093/noajnl/vdag223
URL
https://doi.org/10.1093/noajnl/vdag223
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