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Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors
Open accessAbstract
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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“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).”
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Metadata
- 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 › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Neuroscience › Neurology › Neuroprotection in Cerebral Ischemia
- 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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