Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors

Abstract

Background: Recurrent malignant brain tumors (RMBTs) carry a poor prognosis. Dichloroacetate (DCA) activates mitochondrial oxidative metabolism and has shown activity against several human cancers.

Design: We conducted an open-label study of oral DCA in 15 adults with recurrent WHO grade III - IV gliomas or metastases from a primary cancer outside the central nervous system. The primary objective was detection of a dose limiting toxicity for RMBTs at 4 weeks of treatment, defined as any grade 4 or 5 toxicity, or grade 3 toxicity directly attributable to DCA, based on the National Cancer Institute's Common Toxicity Criteria for Adverse Events, version 4.0. Secondary objectives involved safety, tolerability and hypothesis-generating data on disease status. Dosing was based on haplotype variation in glutathione transferase zeta 1/maleylacetoacetate isomerase (GSTZ1/MAAI), which participates in DCA and tyrosine catabolism.

Results: Eight patients completed at least 1 four week cycle. During this time, no dose-limiting toxicities occurred. No patient withdrew because of lack of tolerance to DCA, although 2 subjects experienced grade 0-1 distal parasthesias that led to elective withdrawal and/or dose-adjustment. All subjects completing at least 1 four week cycle remained clinically stable during this time and remained on DCA for an average of 75.5 days (range 26-312).

Conclusions: Chronic, oral DCA is feasible and well-tolerated in patients with recurrent malignant gliomas and other tumors metastatic to the brain using the dose range established for metabolic diseases. The importance of genetic-based dosing is confirmed and should be incorporated into future trials of chronic DCA administration.

Trial registration: ClinicalTrials.gov NCT01111097.

Conflict of interest statement

Conflict of interest disclosures PWS holds investigator INDs for DCA. DAW is President, Metabolic Solutions, Inc.

Figures

Fig. 1

The PDC catalyzes the rate-limiting step in the aerobic oxidation of glucose and pyruvate and of alanine and lactate, which are in equilibrium with pyruvate. PDC also functionally links cytoplasmic glycolysis with the mitochondrial tricarboxylic acid (TCA) cycle and is thus integral to cellular energetics. Panel A – The 9.5 M Da eukaryotic complex is organized into multiple copies of 3 enzymatic components [19, 20]. The heterotetrameric (α2β2) pyruvate dehydrogenase (E1) decarboxylates pyruvate in the presence of thiamine pyrophosphate (TPP). Dihydrolipoamide acetyltransferase (E2) transfers the acetyl group to a lipoic acid moiety that synthesizes up to 60 molecules of acetyl CoA from reduced coenzyme A per macromolecular complex. Reduced lipoate is reoxidzed by dihydrolipoamide dehydrogenase (E3) in a coupled redox reaction in which NADH is generated. The PDC also utilizes an E3 binding protein (E3BP) to tether the E3 component to the complex’s core. The net reaction thus provides glucose-derived acetyl CoA for the tricarboxylic (TCA) cycle and reducing equivalents (NADH) for the respiratory chain or for anabolic reactions, such as lipid synthesis. Four requisite cofactors enable pyruvate oxidation (thiamine; B1) and the synthesis of coenzyme A (pantothenic acid; B5), acetyl CoA (lipoic acid) and NADH (riboflavin; B2 and niacin; B3). The gene for the E1α subunit is located on the X chromosome and all components of the complex are nuclear encoded. Panel B – Rapid regulation of the PDC is mediated primarily by reversible phosphorylation of up to three serine residues on the E1α subunit, rendering the complex inactive. Phosphorylation of E1α is facilitated by a family of four pyruvate dehydrogenase kinase isoforms (PDK 1–4), whereas two pyruvate dehydrogenase phosphatase isoforms (PDP 1 and 2) dephosphorylate, and activate, the PDC. PDKs themselves are activated by a rise in the intramitochondrial ratio of acetyl CoA:CoA and NADH:NAD+, as well as by an increase in cellular energy charge (ATP:ADP). Pyruvate and certain structurally-related halogenated analogs, such as dichloroacetate (DCA), inhibit PDK activity. PDPs are positively regulated by insulin or magnesium ions and PDP1 can be activated by calcium ions. PDK and PDP isoforms are differentially expressed in tissues and PDK isoforms exhibit variable sensitivity to pyruvate and DCA (Adapted from Stacpoole P. Aging Cell 11:371–377, 2012)

Fig. 2

Bifunctionality of GSTZ1/MAAI. GSTZ1 dehalogenates DCA to the naturally occurring molecule glyoxylate. MAAI isomerizes maleylacetoacetate and maleylacetone, respectively, to fumarylacetoacetate and fumarylacetone

Fig. 3

Relationship between plasma trough DCA and serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations in patient 6, a slow metabolizer of DCA (haplotype: EGM/EGM)

Fig. 4

Pre- and post-DCA (baseline) Pyruvate Breath Test in patient 10, a 61 year old man with GSTZ1/MAAI genotype KGT/KGT

Fig. 5

Pre- and post-DCA (baseline) Pyruvate Breath Tests in patient 11, a 41 year old man with a GSTZ1/MAAI genotype EGM/KGT