Dichloroacetate clinical trial

However, if these trials suggest a favourable efficacy and toxicity, the public will be further motivated to directly fund these efforts and national cancer organisations like the NCI, might be inspired to directly contribute to the design and structure of larger trials.

In that sense, the clinical evaluation of DCA, in addition to its scientific rationale, will be by itself another paradigm shift.

Since the acceptance of this review two important papers have confirmed the novel anticancer effects of DCA in prostate and endometrial cancers: Wong JY et al , Dichloroacetate induces apoptosis in endometrial cancer cells. Gynecol Oncol June ; 3 : — and Gao et al , Dichloroacetate DCA sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation.

Prostate 1 August ; 68 11 : — National Center for Biotechnology Information , U. Journal List Br J Cancer v. Br J Cancer. Published online Sep 2. Author information Article notes Copyright and License information Disclaimer. Copyright , Cancer Research UK.

This article has been cited by other articles in PMC. Abstract The unique metabolism of most solid tumours aerobic glycolysis, i. Keywords: mitochondria, metabolism, apoptosis, potassium channels, positron emission tomography, glycolysis.

The metabolism of cancer cells Most cancers are characterised by aerobic glycolysis GLY , that is, they use glycolysis for energy production, despite the fact that oxygen is present. Open in a separate window. Figure 1. Glycolysis offers an early adaptation to the hypoxic microenvironment in carcinogenesis Gatenby and Gillies recently proposed that as early carcinogenesis often occurs in a hypoxic microenvironment, the transformed cells have to rely on anaerobic GLY for energy production.

Glycolysis is associated with resistance to apoptosis Several of the enzymes involved in glycolysis are also important regulators of apoptosis and gene transcription, suggesting that links between metabolic sensors, cell death and gene transcription are established directly through the enzymes that control metabolism Kim and Dang, Mitochondria and apoptosis Shifting metabolism away from mitochondria GO and towards the cytoplasm GLY , might suppress apoptosis, a form of cell death that is dependent on mitochondrial energy production Figure 2.

Figure 2. DCA reverses the mitochondrial remodeling, unlocking the cancer cells from a state of apoptosis resistance: preclinical work We recently showed that several cancer cell lines non-small cell lung cancer, breast cancer and glioblastoma had hyperpolarised mitochondria, compared with non-cancer cell lines Bonnet et al , , a finding that was first described by Dr Chen at the Dana Farber Institute in the s Chen, Figure 3.

DCA: clinical testing in cancer? Note to proof Since the acceptance of this review two important papers have confirmed the novel anticancer effects of DCA in prostate and endometrial cancers: Wong JY et al , Dichloroacetate induces apoptosis in endometrial cancer cells.

Cancer Cell. Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy. Dichloroacetate DCA sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation.

Mitochondrial membrane potential in living cells. Annu Rev Cell Biol. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Why do cancers have high aerobic glycolysis.

Nat Rev Cancer. Genes Dev. Biochemistry: a pore way to die. Effects of dichloroacetate infusion on human skeletal muscle metabolism at the onset of exercise. Am J Physiol. Why is cancer drug discovery so difficult. Nat Rev Drug Discov. Multifaceted roles of glycolytic enzymes. Trends Biochem Sci.

Cancer's molecular sweet tooth and the Warburg effect. HIFmediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. Glucose catabolism in cancer cells. The type II hexokinase promoter contains functionally active response elements for the tumor suppressor p J Biol Chem.

Brain Dev. Metabolic targeting as an anticancer strategy: dawn of a new era. Sci STKE. Effects of PDH activation by dichloroacetate in human skeletal muscle during exercise in hypoxia. Am J Physiol Endocrinol Metab. Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity.

Cell metabolism in the regulation of programmed cell death. Trends Endocrinol Metab. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. The pharmacology of dichloroacetate. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children.

Efficacy of dichloroacetate as a lactate-lowering drug. J Clin Pharmacol. Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs. Ueber den stoffwechsel der tumoren. Constable: London; Dichloroacetate DCA activates mitochondrial oxidative metabolism and has shown activity against several human cancers. 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.

Secondary objectives involved safety, tolerability and hypothesis-generating data on disease status. Listing a study does not mean it has been evaluated by the U. Federal Government. Read our disclaimer for details.

Last Update Posted : September 22, Study Description. The purpose of this study is to evaluate the safety and tolerability of oral Dichloroacetate DCA in the treatment of recurrent malignant brain tumors RMBTs. RMBTs are defined as either: 1 malignant tumors, originating in the brain, that have recurred at least once or 2 malignant tumors originating elsewhere in the body that have spread to the brain at least once.

Otherwise, there are no limitations to the number of prior recurrences. There are no limitations to the number or types of prior therapies. Detailed Description:. Recurrent malignant brain tumors RMBTs are defined as either: 1 malignant tumors, originating in the brain, that have recurred at least once or 2 malignant tumors originating elsewhere in the body that have spread to the brain at least once.

They share an increasing incidence, clinical and radiographic characteristics, lack of effective therapies, tendency to recur, and poor outcome. Importantly, recurrent malignant brain tumor's shared characteristics may be usefully exploited by an emerging class of biologic agents called metabolic modulators of which Dichloroacetate DCA is the drug in the class most thoroughly investigated clinically. DCA's mechanism of action and tolerability have been extensively demonstrated in the treatment of chronic metabolic disorders.

Furthermore, the preciseness of DCA's mechanism of action appears to target abnormal tumor cell metabolism. Drug Information available for: Sodium dichloroacetate. FDA Resources. Arms and Interventions. The cycles continue unless a serious adverse event occurs or the PI judges the side effects preclude another 30 days of medication. Subjects are given a dose of Dichloroacetate Outcome Measures. Eligibility Criteria.

Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Inclusion Criteria: Subject must be able to consent for self.