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 non-small cell lung cancer (NSCLC).

Materials and methods: This trial was conducted with DCA 6.25 mg/kg orally twice daily in previously treated stage IIIB/IV 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 1 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.

Trial registration: ClinicalTrials.gov NCT01029925.

Fig. 1

In vitro sensitivity to DCA with cisplatin or docetaxel: 54 NSCLC cell lines with IC₅₀ for DCA represented in mM (a). The NSCLC cell lines were also evaluated for IC₅₀ for cisplatin (b) and docetaxel (c) represented in μM. Error bars indicate the standard error based on multiple experiments. Asterisks indicate cell lines for which the IC₅₀ exceeded the highest dose evaluated

Fig. 2

Oxygen consumption rates of NSCLC cell lines exposed to DCA: oxygen consumption rates of HCC-827 (a), SKLU-1 (b), A549 (c) or A427 (d) cells treated with either vehicle (H₂O), 0.5 mM DCA, or 5 mM DCA for 48 h. Error bars indicate the standard error based on multiple experiments

Fig. 3

In vitro combination data evaluating DCA and cisplatin under hypoxic conditions: the sensitivity of four cell lines, HCC-827 (a), SKLU-1 (b), A549 (c), and A427 (d), was evaluated by exposing cells to decreasing concentrations of DCA starting at 10 mM and cisplatin starting at 2 μM. Error bars indicate the standard error based on multiple experiments

Fig. 4

In vitro combination data evaluating DCA and docetaxel under hypoxic conditions: the sensitivity of four cell lines, HCC-827 (a), SKLU-1(b), A549 (c), and A427 (d), was evaluated by exposing cells to decreasing concentrations of DCA starting at 10 mM and docetaxel starting at 2 μM. Error bars indicate the standard error based on multiple experiments