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

Abstract

Objectives Dichloroacetate (DCA) is a highly bioavailable small molecule that inhibits pyruvate dehydrogenase kinase, promoting glucose oxidation and reversing the glycolytic phenotype in preclinical cancer studies. We designed this open label phase II trial to determine the response rate, safety, and tolerability of oral DCA in patients with metastatic breast cancer and advanced stage NSCLC. Materials and Methods This trial was conducted with DCA 6.25 mg/kg orally twice daily in previously treated stage IIIB/IV non-small cell lung cancer (NSCLC) or stage IV breast cancer. Growth inhibition by DCA was also evaluated in a panel of 54 NSCLC cell lines with and without cytotoxic chemotherapeutics (cisplatin and docetaxel) in normoxic and hypoxic conditions. Results and Conclusions Under normoxic conditions in vitro, single agent IC50 was > 2 mM for all evaluated cell lines. Synergy with cisplatin was seen in some cell lines under hypoxic conditions. In the clinical trial, after seven patients were enrolled, the study was closed based on safety concerns. The only breast cancer patient had stable disease after 8 weeks, quickly followed by progression in the brain. Two patients withdrew consent within a week of enrollment. Two patients had disease progression prior to the first scheduled scans. Within one week of initiating DCA, one patient died suddenly of unknown cause, and one experienced a fatal pulmonary embolism. We conclude that patients with previously treated advanced NSCLC did not benefit from oral DCA. In the absence of a larger controlled trial, firm conclusions regarding the association between these adverse events and DCA are unclear. Further development of DCA should be in patients with longer life expectancy, in whom sustained therapeutic levels can be achieved, and potentially in combination with cisplatin.

Targeting of two aspects of metabolism in breast cancer treatment

“…DCA and PENAO are both compounds currently in clinical trials in the treatment of cancer that target different aspects of the cancer metabolic phenotype. [13][14][15]32 Here we demonstrate that PENAO, a novel anti-mitochondrial agent, is effective at low micromolar concentrations against a range of breast cancer cell lines, representing luminal (T-47D and MCF7) and basal (MDA-MB-231 and MDA-MB-468) subtypes of breast cancer, and carcinomas from other tissues (Fig. 1A).…”

“…7,8 DCA has been used in the clinic for lactic acidosis disorders for over 3 decades 9,10 and as an anticancer drug, is one of the most promising candidates that targets metabolism, 11,12 with recent reports indicating its safety in cancer patients. [13][14][15] DCA has been demonstrated to halt tumor growth in vivo, 7,[16][17][18] and in glioblastoma patients could normalize the mitochondria, and induce apoptosis in tumors. 15 The induction of apoptosis is said to be via increased production of reactive oxygen species (ROS) due to increased mitochondrial activity, with decreased polarization of the mitochondrial membrane restoring apoptotic processes.…”

Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation

“…Naive CD4 + T cells also expressed PDHK1, although these cells are predominantly oxidative rather than glycolytic. DCA inhibits PDHK and is currently under investigation in several different types of cancer (38)(39)(40)(41)(42), where it may be effective by inhibition of aerobic glycolysis by suppressing generation of lactate and instead directing glucose to be oxidized in the mitochondria. DCA also can promote ROS in several cancer models that may drive cancer cell senescence (15,38,42).…”

Dichloroacetate alters Warburg metabolism, inhibits cell growth, and increases the X-ray sensitivity of human A549 and H1299 NSC lung cancer cells

“…However, a number of studies strongly suggest that targeting abnormal cancer cell metabolism such as aerobic glycolysis or Warburg metabolism with metabolic agents should be investigated as a potential therapeutic approach in combination with radiation or chemotherapy [14][15][16][17][18][19][20][21]. It has long been known that most cancer cells utilize aerobic glycolysis or Warburg metabolism instead of oxidative phosphorylation for cell energy production [22][23][24][25].…”