Repurposing Dichloroacetate for the Treatment of Multiple Myeloma

Abstract

Multiple myeloma (MM) is an incurable B-cell malignancy and the second most common haematological cancer in the world. MM patients easily develop innate and acquired chemotherapy resistance due to the dynamic gene mutations. The current standard MM treatment is not promising as patients go through cycles of remission and relapse and eventually treatment failure. Therefore, new treatments and management approaches are needed. MM displays a glycolytic phenotype (Warburg effect) that contributes to cancer development, survival, and drug resistance. Dichloroacetate (DCA) is a pyruvate dehydrogenase kinase (PDK) inhibitor that can reverse the glycolytic phenotype. DCA is an inexpensive and bioavailable drug that has been used to treat mitochondrial malfunctions in humans for decades. Studies have shown DCA to have metabolic modulatory and cytotoxicity effects when used at clinically unachievable concentrations (>10 mM) in various cancer types including MM, but there is a lack of evidence of the on-target and anti-cancer effects of DCA when it is used at clinically achievable concentrations. DCA inhibits its own metabolism through inactivation of its only known metabolising enzyme, GSTZ1. It has been hypothesised that GSTZ1 polymorphisms alter a patient’s ability to metabolise DCA, thus it has been proposed that a personalized DCA dose regimen based on GSTZ1 genotype be applied for clinical use. This study examined the on-target and anti-cancer effects of DCA at mechanistically relevant concentrations under clinically relevant conditions in MM cell lines, and investigated the factors contributing to the variable sensitivity to DCA. The clinical implication of DCA was examined in a phase-2 clinical trial in MM patients and the pharmacokinetics and pharmacogenetics of DCA were evaluated. Results of this study showed that DCA at mechanistically relevant concentrations inhibited glycolysis and cell proliferation but did not induce apoptosis in MM cell lines. DCA can act on-target by reducing phosphorylated pyruvate dehydrogenase (pPDH) when used at concentrations achieved in our clinical trial. The effect of DCA in reducing pPDH was cumulative in vitro over time. This study demonstrated that MM cells displayed heterogeneous metabolic profiles. The degree of dependence on glycolysis was a key contributing factor in the sensitivity of MM cells to DCA. Moreover, the growth inhibition effect of DCA required glucose and an active glycolysis pathway. Under hypoxic conditions that mimic the bone marrow (BM) microenvironment (BMM), DCA can induce apoptosis in a non-glycolytic cell line that has the greatest glycolytic reserve and the highest increase in the targets of DCA, PDK1 and PDK3. Thus, DCA can have greater growth inhibition effect and even cytotoxic effects in hypoxic cancers. The clinical use of DCA in cancer had been tested in four clinical trials in solid tumours, with results showing that DCA was well tolerated but there was no direct efficacy information. The clinical use of DCA in haematological cancer patients was investigated through our world-first trial of DCA in MM patients. The results demonstrated that DCA was quickly absorbed and maintained at mechanistically relevant concentrations for inhibition of PDK2. MM patients tolerated DCA well despite having baseline neuropathy. The main side effect of DCA was neuropathy but this was reversible. The disease burden was reduced, and a response was achieved on day 28 in 33% of patients, but this effect was not maintained. A GSTZ1 promoter polymorphism correlated with one patient’s elevated DCA serum levels and side effects, and it may be the driving variant in determining the serum levels of DCA in long-term use. This trial suggested that the DCA dosing regimen needs to be increased in order for it to inhibit the targets PDK1 and PDK3 in cancer patients in future trials. The combination of DCA with common chemotherapy drugs, such as dexamethasone (DEX) and lenalidomide (LEN), significantly decreased the total viable cells numbers compared to when DEX or LEN was used as a single agent. This indicates that DCA is not interfering with the conventional chemotherapy agents. Thus, DCA has the potential to be used as a low-toxicity addition to conventional chemotherapy for the treatment of MM. This study provides DCA dosing guidance and opens windows for future clinical trials in cancers that display a glycolytic phenotype. Show more