Abstract A61: Tumor metabolic remodeling can modulate anticancer drug response: CPI-613 attack on tumor cell mitochondrial metabolism is mediated by metabolite availability
Authors: Stuart Shawn D. , Guardado Moises , Dahan Michael , Bingham Paul M. , Zachar Zuzana 
Published: May 2016

Abstract
We will describe recent progress in understanding the role of cancer metabolic remodeling in determining the response of tumors and tumor cells to a novel, first-in-class clinical agent class selectively targeting cancer cell mitochondrial metabolism.
The reconfiguration of mitochondrial metabolism in cancer in general, and the tricarboxylic acid (TCA) cycle in particular, presents a rich source of potential therapeutic targets. Pyruvate dehydrogenase (PDH) and alpha ketoglutarate dehydrogenase (KGDH) are two gatekeeper enzymes regulating carbon flux into the mitochondrial TCA cycle. A key component of the altered regulatory processes in cancer is lipoic acid (lipoate), which not only functions as a cofactor for both PDH and KGDH, but also as source of regulatory information. Moreover, the lipoate-sensitive regulatory components of PDH and KGDH are substantially reconfigured in tumor cells, providing cancer-specific targets that can be successfully attacked with properly designed lipoate analogs.
We developed and characterized CPI-613, a lipoic acid analog, which selectively targets mitochondrial metabolism in tumor cells by mobilizing lipoate-sensitive, cancer-specific regulation of PDH and KGDH, shutting down the two enzymes and thereby choking carbon flow through the TCA cycle. This attack on mitochondrial metabolism redundantly activates multiple cell death pathways (Zachar, et al., 2011, J Mol Med 89, 1137; Stuart, et al., 2014, Cancer&Metab 2, 4). In vitro, CPI-613 is uniformly effective in killing tumor cell lines (more than 50 tumor lines tested to date). Moreover, these drugs have produced compelling clinical responses (including complete remissions) in some, but not all patients with advanced, refractory, heavily pre-treated cancers in initial Phase I/II clinical trials (Pardee et al., 2014, Clin Cancer Res 20:5255).
In an effort to explore the mechanisms of CPI-613 activity and characterize the reasons for differential patient responses, we have shown that the kinetics of the cancer cell death response to CPI-613 is profoundly affected by the carbon sources available to the cell (Zachar, et al., 2011, J Mol Med 89, 1137). For example, in media where pyruvate and glutamine (capable of producing net ATP synthesis only in the mitochondrial compartment) are the major carbon sources, death is rapid, completed within 4 hours (op cit). In contrast, when glucose is substituted for pyruvate, the cell death programs take up to 48 hours to complete. We have analyzed the mechanistic basis of this and related observations, including steady state and flux metabolomics, pharmacological inhibitors of non-TCA metabolic pathways, and manipulation of media composition to systematically characterize these dramatic effects of nutrient availability on cancer cell drug response.
Our results demonstrate that CPI-613 induced inactivation of tumor cell KGDH is modulated by the potency of mitochondrial redox detoxification (Stuart, et al., 2014, Cancer&Metab 2, 4). Given that various metabolic pathways (for example, glycolysis) can ultimately contribute to mitochondrial ROS detoxification potential, it appears that substrate availability powerfully influences the cellular response to CPI-613.
These insights open a number of fundamentally new approaches to increasing the fraction of patients who respond strongly to CPI-613 in the clinic. We will also report pre-clinical studies targeted at allowing planned future clinical trials to exploit these new insights.
Citation Format: Shawn D. Stuart, Moises Guardado, Michael Dahan, Paul M. Bingham, Zuzana Zachar. Tumor metabolic remodeling can modulate anticancer drug response: CPI-613 attack on tumor cell mitochondrial metabolism is mediated by metabolite availability. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A61.