Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors
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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.
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Drugs that inhibit glycolysis such as dichloroacetic acid (DCA), which inhibits PDK activity, have been tested.
“This knowledge has led to the testing of drugs that inhibit glycolysis such as dichloroacetic acid (DCA), which inhibits PDK activity (Dunbar et al., 2014).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Dunbar et al., 2014
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- Authors
- Dunbar, E. M., Coats, B. S., Shroads, A. L., Langaee, T., Lew, A., Forder, J. R., Shuster, J. J., Wagner, D. A., & Stacpoole, P. W.
- Affiliations
- University of Florida Health (US)
- University of Florida (US)
- Metabolic Solutions (US)
- Corresponding author
- Stacpoole, P. W.
- Venue
- Investigational New Drugs
- Published
- 2013-12-03
- Volume
- 32
- Issue
- 3
- Pages
- 452-464
- ISSN
- 0167-6997 (ISSN-L)
- 1573-0646
- PMC
- PMC4455946
- OpenAlex
- W2017529554
- Cited by
- 241
- References
- 50
- Citations by year
- 2026: 30 · 2025: 18 · 2024: 17 · 2023: 15 · 2022: 16 · 2021: 18 · 2020: 18 · 2019: 29 · 2018: 20 · 2017: 17 · 2016: 15 · 2015: 19 · 2014: 9
- FWCI
- 7.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Investigational New Drugs (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000064)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Keywords
- dichloroacetate, glioma, brain metastases, dose-limiting toxicity, drug safety and tolerability, mitochondrial oxidative metabolism
- MeSH terms
- Acetone, Adult, Aged, Alanine Transaminase, Antineoplastic Agents, Aspartate Aminotransferases, Brain Neoplasms, Breath Tests, Dichloroacetic Acid, Female, Glutathione Transferase, Haplotypes, Humans, Male, Maleates, Middle Aged, Pyruvic Acid
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