Abstract IA07: Exploiting cancer metabolism for cancer therapy

Abstract

Abstract I will describe two approaches for cancer therapy, which exploit distinct intracellular metabolism in cancer cells to selectively eradicate them. In the first part of my presentation I will describe how we could target hexokinase 2 for cancer therapy, and without any overt physiological consequences. In the second part of the presentation I will describe how we could exploit high levels of reactive oxygen species (ROS) in cancer cells displaying hyperactive Akt to selectively eradicate these cancer cells and to evade chemoresistance induced by hyperactivation of Akt. Hexokinases, which catalyze the first committed step in glucose metabolism, play a vital role in the cellular uptake and utilization of glucose. By catalyzing the ATP-dependent phosphorylation of glucose to yield glucose 6-phosphate (G6P), hexokinases influence not only the magnitude, but also the direction, of glucose flux within cells. Four major hexokinase isoforms, encoded by separate genes, have been described in mammalian tissues— denoted as HK1, HK2, HK3, and HK4 (also known as glucokinase). A fifth hexokinase isoform that is not yet fully characterized has been recently discovered. The high affinity isoforms HK1, HK2, and HK3 each have Km values in the micromolar range, and are characterized by sensitivity to feedback inhibition by their principal reaction product, glucose 6-phosphate. In contrast, HK4 exhibits a relatively low affinity for glucose (Km ~6 mM). HK1 and HK2 have unique ability to bind the outer mitochondrial membrane. This binding is dynamic and regulated and is thought to couple oxidative phosphorylation and glycolysis. The binding of hexokinases to the mitochondria is also important for cell survival. The ubiquitous HK1 isoform appears to be constitutively expressed in most tissues. HK2, however, is expressed at high levels in embryonic tissues, but only in limited number of adult tissues such as fat, skeletal muscles, and heart. In cancer cells HK2 expression is dramatically induced, distinguishing cancer cells from normal cells, and therefore targeting HK2 could be exploited for cancer therapy. The high levels of HK2 expression in cancer cells is also manifested by the use of positron emission tomography (PET) to visualize tumors in vivo. PET is used following injection of [18F] fluoro-2-deoxyglucose (FDG), which is then being taken by glycolytic cancer cells and is phosphorylated by hexokinase to form FDG-phosphate, which can be detected by PET. Although germ line deletion of HK2 causes embryonic lethality we had shown that its systemic deletion in adult mice is well tolerated, and without adverse physiological consequences. Therefore it could be an ideal target for cancer therapy. Indeed we showed that systemic deletion of HK2 inhibits lung and breast cancer progression in mice. Both lung and breast cancer cells also express HK1. By contrast hepatocellular carcinoma (HCC) cells express only HK2, and therefore we expect that they would be much more dependent on HK2. The serine/threonine kinase Akt is perhaps the most frequently hyperactivated kinase in human cancer and it hyperactivation exerts chemoresistance. However, the most evolutionarily conserved function of Akt is in the regulation of metabolism and energy metabolism. As a consequence of high energy metabolism exerted by hyperactivation of Akt in cancer cells, there is a marked increase in intracellular ROS. Although activation of Akt exerts resistance to multiple apoptotic stimuli, Akt could not protect from ROS-induced cell death. Therefore the high intracellular ROS following hyperactivation of Akt renders cells more sensitive to ROS. This is exploited to selectively eradicate cancer cells that display hyperactivation of Akt. Citation Format: Nissim Hay. Exploiting cancer metabolism for cancer therapy. [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 IA07.