A Phase I, Open-Labeled, Single-Arm, Dose Escalation, Clinical and Pharmacology Study of Dichloroacetate (DCA) in Patients With Recurrent and/or Metastatic Solid Tumours

03:34 EDT 1st September 2014 | BioPortfolio

Summary

Dichloroacetate (DCA) is a small molecule that has been used for years to treat lactic acidosis and rare metabolic disorders in humans. Further testing now shows that it may suppress the growth of human cancer cells. Tests of DCA on human cells cultured outside of the body found that it killed lung, breast, and brain cancer cells, without affecting human normal cells. Tumors in rats that were infected with human tumors also shrank considerably. Most cancers are characterized by a resistance to apoptosis (cell death that removes abnormal cells) that makes them more likely to grow as well as be resistant to most cancer treatments. Plus, many current cancer treatments kill both cancerous and healthy cells and are highly toxic. DCA works by reversing the damage to the mitochondria that is present in cancer cells, thus reactivating the apoptosis (cell death) mechanism in them. The result is the death of the cancer cells. This mitochondrial reactivation presents an entirely new approach to treating cancer.

DCA is known to be relatively well tolerated with few significant side effects and its selectivity, effectiveness and ease of delivery (oral) make it an attractive opportunity. It is hoped that one day this treatment may become a safe and effective treatment, either along or in conjunction with other treatments, for many forms of cancer.

Description

As cancer cells have a hyperpolarized mitochondrial membrane and deficiency in Kv channel expression, it was postulated that the reversal of this observation may increase apoptosis and inhibit tumor growth. Bonnet and colleagues reported that the administration of DCA led to the switch from glycolysis to oxidative phosphorylation in the Krebs Cycle through inhibition of PDHK. This was associated with an increase in the production of reactive oxygen species and a decrease in hyperpolarization of the inner mitochondrial membrane, leading to efflux of proapoptotic proteins and apoptosis as measured by increased in TUNEL-positive cells. In addition, DCA also decreased the expression of survivin, an anti-apoptotic protein. DCA upregulated the expression of Kv channels in cancer cells, leading to efflux of potassium ions and further increased the proapoptotic effect of DCA. Such change in energy metabolism and apoptosis was not observed in normal cells. DCA was also shown to inhibit tumor growth both in vitro and in vivo. Thus, inhibition of PDHK by DCA represents a novel anti-cancer therapy target with reasonable toxicities to normal tissue. It is therefore of interest to study DCA in refractory cancer patients.

Although the bioavailability was only 50-60% in normal subjects treated with 2.5 microgram/kg of DCA , in a study using clinically relevant dose of DCA at 50 mg/kg, the bioavailability was 100% in health volunteers. DCA administered at 50 mg/kg/day can achieve plasma concentrations above those require for inhibition of PHDK, the target enzyme for at least 24 hours, without exceeding the concentration for maximal lactate lowering. There was a high incidence of peripheral neuropathy in adults with MELAS after administration of DCA at 50 mg/kg/day for 6 months, but peripheral neuropathy is part of the MELAS syndrome, and many adult patients with MELAS develop diabetes mellitus, which commonly presents with peripheral neuropathy. In the contrary, no peripheral neuropathy was observed in children with congenital acidosis after prolonged treatment with DCA at 50 mg/kg/day up to 2 years. Therefore, with exclusion of patients with any grade 2 or higher peripheral neuropathy and with careful monitoring of peripheral neuropathy using monofilaments, the likelihood of developing severe peripheral neuropathy in adult cancer patients should be minimized. Given the presence of significant neuropathy in adult patients with MELAS after treatment with DCA at 25 mg/kg/day, it is judged to be safe and reasonable to establish the starting dose at 12.5 mg/kg/day in adult cancer patients.

Study Design

Allocation: Non-Randomized, Control: Uncontrolled, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Conditions

Neoplasms

Intervention

Dichloroacetate

Location

Cross Cancer Institute
Edmonton
Alberta
Canada
T6G 1Z2

Status

Recruiting

Source

Alberta Health Services

Results (where available)

View Results

Links

Clinical Trials [18 Associated Clinical Trials listed on BioPortfolio]

Evaluating the Effectiveness of a Dichloroacetate in MELAS Syndrome

Patients with the MELAS syndrome experience devastating mental impairment. This study will evaluate the effectiveness of the drug dichloroacetate (DCA) to reduce the symptoms of MELAS.

Prevention of Dichloroacetate Toxicity

This is a study to determine the safety of dichloroacetate (DCA) with a low-tyrosine diet given with or without nitisinone (NTBC) in children with chronic lactic acidosis (CLA).

Dichloroacetate Kinetics, Metabolism and Toxicology

Dichloroacetate (DCA) is a product of water chlorination and a metabolite of certain industrial solvents, thus making it a chemical of environmental concern. However, DCA is also used as a...

Dichloroacetate (DCA) for the Treatment of Pulmonary Arterial Hypertension

Hypothesis: The small molecule and metabolic modulator Dichloroacetate (DCA) is safe, tolerated as a potential therapy in patients with moderate or severe Pulmonary Arterial Hypertension (...

Pharmacotoxicology of Trichloroethylene Metabolites: Kinetic Study of Dichloroacetate (DCA) in Persons Homozygous for KRT Versus Wildtype

Specific Aim 2: Establish the relationship between human MAAI haplotype and DCA and tyrosine metabolism. This aim tests the postulates that MAAI haplotype determines 1) dose-dependent DCA...

PubMed Articles [562 Associated PubMed Articles listed on BioPortfolio]

Dichloroacetate modulates cytokines toward T helper 1 function via induction of the interleukin-12-interferon-γ pathway.

Dichloroacetate (DCA) is one of the new, promising anticancer drugs. DCA restores normal mitochondrial function and enables cancer cells to undergo apoptosis. In addition, DCA was found to modulate ce...

Neuroendocrine tumour, mucinous adenocarcinoma and signet-ring cell carcinoma of the appendix: three cases and review of literature.

Appendiceal neoplasms are relatively common tumours. Although these tumours are often associated with signs and symptoms of acute appendicitis, most appendiceal neoplasms are clinically silent. Append...

Dichloroacetate should be considered with platinum-based chemotherapy in hypoxic tumors rather than as a single agent in advanced non-small cell lung cancer.

Dichloroacetate (DCA) is a highly bioavailable small molecule that inhibits pyruvate dehydrogenase kinase, promoting glucose oxidation and reversing the glycolytic phenotype in preclinical cancer stud...

Metabolism targeting therapy of dichloroacetate-loaded electrospun mats on colorectal cancer.

Abstract Differences in energy metabolism between tumor cells and normal cells offer an attractive avenue of research into drug targets for tumor therapy. The use of a metabolic modulator (sodium dich...

Cutaneous mesenchymal tumours: an update.

Mesenchymal tumours of the skin and subcutis are rare and characterised by extreme clinicopathological heterogeneity. Although all neoplasms of deeper soft tissue neoplasms may also occur in a superfi...

Medical and Biotech [MESH] Definitions

A collective term for precoordinated organ/neoplasm headings locating neoplasms by organ, as BRAIN NEOPLASMS; DUODENAL NEOPLASMS; LIVER NEOPLASMS; etc.

An acetic acid derivative that is a metabolite of TRICHLOROETHYLENE and is formed during chlorine disinfection of drinking water. It has effects on GLUCOSE metabolism, lowers LACTATE, and activates the PYRUVATE DEHYDROGENASE COMPLEX.

Cancers or tumors of the MAXILLA or MANDIBLE unspecified. For neoplasms of the maxilla, MAXILLARY NEOPLASMS is available and of the mandible, MANDIBULAR NEOPLASMS is available.

Benign and malignant neoplasms which occur within the substance of the spinal cord (intramedullary neoplasms) or in the space between the dura and spinal cord (intradural extramedullary neoplasms). The majority of intramedullary spinal tumors are primary CNS neoplasms including ASTROCYTOMA; EPENDYMOMA; and LIPOMA. Intramedullary neoplasms are often associated with SYRINGOMYELIA. The most frequent histologic types of intradural-extramedullary tumors are MENINGIOMA and NEUROFIBROMA.

Neoplasms located in the vasculature system, such as ARTERIES and VEINS. They are differentiated from neoplasms of vascular tissue (NEOPLASMS, VASCULAR TISSUE), such as ANGIOFIBROMA or HEMANGIOMA.

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