CTNI-13. SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMIC EFFECTS OF DICHLOROACETATE IN PATIENTS WITH RECURRENT GLIOBLASTOMA

Abstract Glioblastomas (GBM) are characterized by the Warburg effect, driven by upregulation of pyruvate dehydrogenase kinase (PDK) that phosphorylates and inhibits pyruvate dehydrogenase complex (PDC) E1a (PDHA1). Dichloroacetate (DCA), a PDK inhibitor used extensively in children with metabolic diseases, restores PDC activity, readily crosses the blood-brain barrier, reverses Warburg metabolism, and induces selective tumor apoptosis. This multicenter FDA-funded trial evaluated the safety, pharmacokinetics, and pharmacodynamics of oral DCA in recurrent GBM patients, sequentially allocated to receive DCA or no DCA, one week prior to debulking surgery. All patients received DCA after surgical recovery. Plasma was collected to measure DCA and lactate. Enhancing and non-enhancing tumor tissues were obtained at surgery to measure expression of p-PDHA1, PDK 1-4 and proliferation markers. Currently, data are available on 34 patients (mean age 60). Only one patient experienced drug-related adverse effects (peripheral neuropathy). Pretreatment lactate levels were similar between both arms (2.10 and 2.15mmol/l, p=0.85). At surgery, DCA-treated patients had lower plasma lactate (1.60 vs 2.51mmol/l; p=0.01) than untreated patients. In contrast-enhanced tumor samples, DCA-treated patients had lower p-PDHA1, PDK4, and VEGF-α (all p≤0.002) compared to patients without DCA. In non-enhancing tumors, no differences in p-PDHA1 and PDK 1-4 expression were found, but PCNA and PGK1 levels were reduced and ERK1/2 was increased in DCA-treated patients (all p≤ 0.03), consistent with decreased tumor proliferation. After 8 weeks of DCA post-surgery, plasma lactate decreased 54% from baseline (1.04 vs 2.24mmol/l, p<0.0001). Our findings align with DCA‘s known action and suggest a shift towards aerobic respiration and reduced tumor cell proliferation. We conclude DCA is safe and well-tolerated, reversed Warburg metabolism and tumor proliferation markers, and lowered plasma lactate. PDK expression and lactate levels are associated with worse cancer outcomes. Combining DCA with standard radiation and chemotherapy could improve outcomes of newly diagnosed GBM patients.