GSTZ1 genotypes correlate with dichloroacetate pharmacokinetics and chronic side effects in multiple myeloma patients in a pilot phase 2 clinical trial

Abstract

Dichloroacetate (DCA) is an investigational drug targeting the glycolytic hallmark of cancer by inhibiting pyruvate dehydrogenase kinases (PDK). It is metabolized by GSTZ1, which has common polymorphisms altering enzyme or promoter activity. GSTZ1 is also irreversibly inactivated by DCA. In the first clinical trial of DCA in a hematological malignancy, DiCAM (DiChloroAcetate in Myeloma), we have examined the relationship between DCA concentrations, GSTZ1 genotype, side effects, and patient response. DiCAM recruited seven myeloma patients in partial remission. DCA was administered orally for 3 months with a loading dose. Pharmacokinetics were performed on day 1 and 8. Trough and peak concentrations of DCA were measured monthly. GSTZ1 genotypes were correlated with drug concentrations, tolerability, and disease outcomes. One patient responded and two patients showed a partial response after one month of DCA treatment, which included the loading dose. The initial half‐life of DCA was shorter in two patients, correlating with heterozygosity for GSTZ1*A genotype, a high enzyme activity variant. Over 3 months, one patient maintained DCA trough concentrations approximately threefold higher than other patients, which correlated with a low activity promoter genotype (−1002A, rs7160195) for GSTZ1. This patient displayed the strongest response, but also the strongest neuropathy. Overall, serum concentrations of DCA were sufficient to inhibit the constitutive target PDK2, but unlikely to inhibit targets induced in cancer. Promoter GSTZ1 polymorphisms may be important determinants of DCA concentrations and neuropathy during chronic treatment. Novel dosing regimens may be necessary to achieve effective DCA concentrations in most cancer patients while avoiding neuropathy.

Effects of Multiple Doses of Dichloroacetate on GSTZ1 Expression and Activity in Liver and Extrahepatic Tissues of Young and Adult Rats

“…However, the chronic effects of DCA administration vary among individuals. Diversity in GSTZ1 haplotype is known to affect the pharmacokinetics of DCA (Board and Anders, 2011;Li et al, 2012;Zhong et al, 2014;Tian et al, 2019). Other variables contributing to differential responses to DCA are age (Kaufmann et al, 2006;Stacpoole, 2011;Shroads et al, 2012;Abdelmalak et al, 2013) and tissue chloride concentrations, as chloride slows the inactivation of GSTZ1 by DCA (Zhong et al, 2014;Jahn et al, 2018;Smeltz et al, 2019).…”

DRUG REPURPOSING—Overcoming the translational hurdles to clinical use

“…The work of Tian et al in this Journal is therefore very timely. The team has taken an area of clinical need and has used a very cheap off patent drug that targets a key glycolytic pathway in cancer.…”

Pyruvate dehydrogenase kinases (PDKs): an overview toward clinical applications

“…In a phase II clinical study of 10 multiple myeloma patients, parenteral nutrition was the only significant side effect after long-term use and was reversible. DCA at 6.25 mg/kg b.i.d did not seriously worsen parenteral nutrition, so DCA can be used for patients with peripheral neuropathy [99]. Despite the therapeutic and economic benefits of The second category is inhibitors that act on dilipoic acid pocket compounds, such as Nov3r, AZD7545 and CP1613 [96,[101][102][103].…”

“…In a phase II clinical study of 10 multiple myeloma patients, parenteral nutrition was the only significant side effect after long-term use and was reversible. DCA at 6.25 mg/kg b.i.d did not seriously worsen parenteral nutrition, so DCA can be used for patients with peripheral neuropathy [ 99 ]. Despite the therapeutic and economic benefits of DCA, it has been used in limited situations, such as life-threating lactic acidosis induced by PDH-E1α deficiency or sepsis for the short term because of its toxicities, including neuropathy and hepatic tumorigenesis, poor pharmacokinetics, and low potency and selectivity [ 100 ].…”