Investigational cancer drugs targeting cell metabolism in clinical development

Abstract

Introduction: Malignant cell transformation and tumor progression are associated with alterations in glycolysis, fatty acid synthesis, amino acid delivery and production of reactive oxygen species. With increased understanding of the role of metabolism in tumors, there has been interest in developing agents that target tumor specific metabolic pathways. Numerous promising agents targeting altered metabolic pathways are currently in Phase I - III clinical trials. Areas covered: This paper reviews the early phase clinical trial development of these agents and provides perspective on the future direction of this emerging field. Specifically, the authors describe novel and repurposed therapies, focusing on the effects of each agent on tumor metabolism and results from relevant Phase I and II clinical trials. Expert opinion: Metabolism modulating agents, alone and in combinations with other classes of agents, have shown efficacy in the treatment of neoplasm, which, the authors believe, will bear positive results in future studies. Because of the significant crosstalk between metabolic pathways and oncogenic signaling pathways, the authors also believe that combining metabolic modifiers with targeted agents will be an important strategy. An increased understanding of cancer metabolism, in addition to the continued study of metabolic modulators, should lead to further advances in this nascent therapeutic field in the future.

Keywords: Phase I and II; cancer; cell metabolism; drugs; metabolism modulating agents.

Figure 1. Metabolic pathways and oncogenic signaling in tumor cells

Malignant transformation is associated with derangements of major metabolic pathways, including glycolysis, mitochondrial metabolism, amino acid metabolism, and fatty acid synthesis. 1,3 dPG: 1,3-biphosphoglyceric acid; 2-HG: 2-hydroxyglutarate; 2PG: 2-phosphoglyceric acid; 3PG: 3-phosphoglyceric acid; ACC: Acetyl-CoA carboxylase; ACL: ATP citrate lyase; CAIX: Carbonic anhydrase IX; CoA: Coenzyme A; F1,6P: Fructose 1,6-phosphate; F6P: Fructose 6-phosphate; FAS: Fatty acid synthase; G6P: Glucose 6-phosphate; GAP: Glyceraldehyde 3-phosphate; GLUT: Glucose transporter proteins; GSH: Reduced glutathione; GSR: Glutathione reductase; GSSG: Glutathi-one disulfide; HIF-1: Hypoxia-inducible factor 1; HK: Hexokinase; IDH1: Isocitrate dehydrogenase 1; IDH2: Isocitrate dehydrogenase 2; MCT1: Lactate transporter; MCT4: Monocarboxylate transporter 4; OAA: Oxaloacetic acid; PD: Pyruvate dehydrogenase; PDK: Pyruvate dehydrogenase kinase; PEP: Phosphoenolpyruvic acid; PKM2: Pyruvate kinase isozyme 2; ROS: Reactive oxygen species; SOD: Superoxide dismutase; TCA: Tricarboxylic acid cycle; α-KG: α-ketoglutarate.

Figure 2. Agents that modulate glycolysis

Multiple agents have shown the propensity to inhibit various steps of the glycolytic pathway. Silybin is an inhibitor of GLUT transporter proteins, londamine inhibits hexokinase, 2-deoxyglucose acts as a competitive inhibitor of glucose metabolism, AZD3965 is a MCT1 inhibitor, TLN-232 inhibits the PKM2 dimer, CPI-613 is a small molecular inhibitor of PDH and α-ketoglutarate dehydrogenase, and dichloroacetate (DCA) inhibits PDK. CoA: Coenzyme A; G6P: Glucose-6-phosphate; HK: Hexokinase; MCT: Monocarboxylate transporter; PDH: Pyruvate dehydrogenase complex; PDK: Pyruvate dehydrogenase kinase; PFK1: Phosphofructokinase 1; PKM: Pyrvate kinase isoenzyme; TCA: Tricarboxylic acid cycle.

Figure 3. Agents that modulate reactive oxygen species

Agents targeting multiple steps of mitochondrial mechanism have been evaluated in early phase clinical trials. Agents that augment production of reactive oxygen species include mangafodipir/calmangafodipir, motexafin, ARQ-501, ele-sclomol, arsenic trioxide, STA-4783, 2-ME, ENMD-1198, and ATN-224. Other agents affect mitochondrial metabolism via alternate routes, including phenylethyl isothiocyanate downregulation of glutathione, buthionine sulphoximine inhibition of GSH synthesis, and imexon depletion of GSH via thiol binding. GSH: Reduced glutathione; GSR: Glutathione reductase; GSSG: Glutathione disulfide; H2O: Water; H2O2: Hydrogen peroxide; O2: Oxygen; ROS: Reactive oxygen species; SOD: Superoxide dismutase.

Figure 4. Agents that modulate fatty acid synthesis

Limited agents that act on fatty acid synthesis are in clinical development, but the fatty acid synthase inhibitor, epigallo-catechin gallate has been evaluated in phase 1 and 2 trials. ACC: Acetyl-CoA carboxylase; ACL: Adenosine triphosphate citrate lyase; CoA: Coenzyme A; EGCG: Epigallocatechin gallate; FAS: Fatty acid synthase; NAD: Nicotinamide adenine dinucleotide; OAA: Oxaloacetic acid; TCA: Tricarboxylic acid cycle.

Figure 5. Agents that modulate the carbonic anhydrase IX pathway

Carbonic anhydrase IX is upregulated in numerous malignancies, and cG250, the anti-CAIX monoclonal antibody, and CAIX inhibitor E7070 have been evaluated in clinical trials. CAIX: Carbonic anhydrase 9; CO2: Carbon dioxide; H+: Hydrogen; H2O: Water; HCO3−: Bicarbonate.