Abstract 4545: Anticancer activity of elesclomol correlates with low LDH levels and active mitochondrial respiration

Abstract

Abstract Elesclomol is a first-in-class investigational drug that exerts anticancer activity through the elevation of reactive oxygen species (ROS). Our previous studies revealed that elesclomol selectively chelates copper and generates ROS via reduction of Cu(II) to Cu(I). In a Phase 3 trial in metastatic melanoma, the level of baseline lactate dehydrogenase (LDH) in patients emerged as an important prognostic factor for treatment outcomes with elesclomol. Additional investigations were undertaken to evaluate the relation between elesclomol activity and LDH levels. Because the copper redox reactions necessary for elesclomol activity can be influenced by changes in cellular metabolic properties, we investigated whether elesclomol activity varies between normoxic conditions (active mitochondrial respiration, low LDH) and hypoxic conditions (decreased mitochondrial respiration, high LDH). To assess the influence of hypoxic conditions, we evaluated elesclomol activity under several situations in which cells express high levels of Hypoxia Inducible Factor-1α (HIF1α), a transcription factor that induces a complete set of glycolytic enzymes, including LDH, and switches off glycolytic carbon flow to mitochondria. First, an increase in the level of HIF1α protein was observed in M14 melanoma cells at low oxygen level or high cell density. Elesclomol showed decreased cytotoxicity under both of these conditions. Second, we evaluated lines within the same cancer phenotype but showing distinct levels of HIF1α, and found that the high-HIF1α-expressing Caki-2 renal cancer line was resistant to elesclomol, while lower-HIF1α-expressing renal cancer cell lines were sensitive to elesclomol. Third, we assessed HIF1α levels and elesclomol activity in cells treated with CoCl2, a chemical mimetic of hypoxia. High levels of HIF1α induction were present in M14 cells treated with CoCl2, and elesclomol was significantly less active in these cells. The addition of oxamate, which selectively inhibits LDHA and activates pyruvate entry into mitochondria, restored the activity of elesclomol in the CoCl2-treated cells. These results support the hypothesis that elesclomol is more active under normoxic conditions (low LDH) and less active under hypoxic conditions (high LDH), consistent with the clinical findings. The results may be important for identifying patient populations for future clinical development of elesclomol. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4545.