Targeting Oncometabolites in Peritoneal Cancers: Preclinical Insights and Therapeutic Strategies

Abstract

Peritoneal cancers present significant clinical challenges with poor prognosis. Understanding the role of cancer cell metabolism and cancer-promoting metabolites in peritoneal cancers can provide new insights into the mechanisms that drive tumor progression and can identify novel therapeutic targets and biomarkers for early detection, prognosis, and treatment response. Cancer cells dynamically reprogram their metabolism to facilitate tumor growth and overcome metabolic stress, with cancer-promoting metabolites such as kynurenines, lactate, and sphingosine-1-phosphate promoting cell proliferation, angiogenesis, and immune evasion. Targeting cancer-promoting metabolites could also lead to the development of effective combinatorial and adjuvant therapies involving metabolic inhibitors for the treatment of peritoneal cancers. With the observed metabolomic heterogeneity in cancer patients, defining peritoneal cancer metabolome and cancer-promoting metabolites holds great promise for improving outcomes for patients with peritoneal tumors and advancing the field of precision cancer medicine. This review provides an overview of the metabolic signatures of peritoneal cancer cells, explores the role of cancer-promoting metabolites as potential therapeutic targets, and discusses the implications for advancing precision cancer medicine in peritoneal cancers.

Keywords: aerobic glycolysis; cancer metabolism; metabolite; metabolome; metabolomics; oncometabolite; peritoneal cancers; tumor microenvironment.

Figure 1

Subtypes of peritoneal cancers. Peritoneal Cancers can be categorized as primary and secondary, depending on their origins. Primary peritoneal cancers include peritoneal mesothelioma, peritoneal serous carcinoma, leiomyomatosis peritonealis disseminata, desmoplastic round cell tumors, and solitary fibrous tumors. Secondary peritoneal cancers of intra-peritoneal origin are appendiceal, colorectal, endometrial, gastric, ovarian, pancreatic cancers, and sarcomas. Peritoneal cancers of extra-peritoneal origin include breast, kidney, and lung cancers, as well as melanoma.

Figure 2

Oncometabolites from glucose metabolism. Oncometabolites derived from dysregulated glucose metabolism in peritoneal cancers, including glycolysis, the tricarboxylic acid cycle (TCA cycle), and the pentose phosphate pathway (PPP), are presented. Oncometabolites arising from deregulated TCA cycle include pyruvate, α-ketoglutarate (α-KG), succinate, fumarate, and 2-hydroxyglutarate (2-HG). Oncometabolites from dysregulated glycolytic shift include increased levels of glucose, glyceraldehyde-3-phosphate (G3P), pyruvate, and lactate. Oncometabolites derived from the PPP are nicotinamide adenine dinucleotide phosphate (NADPH), G3P, and 6-phosphogluconate (6PG). Other abbreviations are GLUT, Glucose Transporters; F6P, Fructose-6-phosphate; DHAP, Dihydroxyacetone phosphate; OAA, Oxaloacetate; and RuBP, Ribulose-1,5-bisphosphate.

Figure 3

Oncometabolites from lipid metabolism. Lipid oncometabolites, generated by dysregulated metabolism of cholesterol, fatty acids, and triglycerides in peritoneal cancers are illustrated. Oncometabolites resulting from deregulated cholesterol metabolism are muricholic acid (MCA), 23-lactone, 22β-dihydroxy cholesterol (22βDHC), and 1,25-dihydroxyvitamin D3-26, 23-lactone (Vitamin D3). Oncometabolites generated by deregulated fatty acid metabolism include malonyl CoA, tridecanoic acid, tetradecanoic acid, and octadecanoic acid. Deregulated fatty acid metabolism also results in the production of signaling lipids such as ceramide (18:1), lysophosphatidic acid (LPA), and sphingolipids (SPL). Additionally, potential oncometabolites resulting from lipid metabolism in peritoneal cancers include the metabolites derived from the lipolysis of storage triglycerides (TG). The metabolites denoted by abbreviations are FFA, Free Fatty Acids; CD-36, Fatty acid translocase CD36; PUFAs, Polyunsaturated fatty acids; MUFAs, Monounsaturated fatty acids; α-KG, α-ketoglutarate; OAA, Oxaloacetate; PA, Phosphatidic acids; SFA, Saturated fatty acids; and G3P, Glyceraldehyde-3-phosphate.

Figure 4

Oncometabolites from amino acid metabolism. Dysregulated metabolism of glutamine (Gln), glutamic acid (Glu), tryptophan (Trp), methionine (Met), alanine (Ala), arginine (Arg), and glycine (Gly) generate several oncogenic metabolites in peritoneal cancers. These metabolites include glutamine (Gln), glutamate (Glu), oxaloacetate (OAA), glutamyl alanine (GA), and α-ketoglutarate (α-KG) from glutamine (Gln) metabolism; α-amino butyric acid (GABA) from glutamine-glutamate metabolism; 3-methyl alanine (3MA) from alanine (Ala) metabolism; glutamyl alanine (GA) from glutamine-alanine metabolism; sarcosine from glycine (Gly) metabolism; homocysteine (HC); and S-adenosyl methionine (SAM) from methionine metabolism; ornithine (Orn), polyamines (PA), and depletion of arginine (Arg) from arginine metabolism; and kynurenine (Kyn) from tryptophan (Trp) metabolism; and glutathione (GSH) from Cysteine (Cys)-glutamate-glycine metabolism. Other abbreviations used are SAH, S-adenosyl homocysteine; Cys-Cysteine; GSH, glutathione-reduced; GSSG, Glutathione-oxidized; Pyr, Pyruvate; OAA, Oxaloacetate; Asp, Aspartate; and NAD+, Nicotinamide adenine dinucleotide.

Figure 5

Oncometabolites from nucleotide metabolism. Oncogenic intermediates are generated by the deregulated metabolism of purines, pyrimidines, and their cofactors in peritoneal cancers. Oncometabolites resulting from purine metabolism include inosine monophosphate (IMP) and 5-phosphoribosyl-1-pyrophosphate (PRPP) while oncometabolites generated by pyrimidine metabolism include dihydroorotate (DHO), orotate, PRPP, and thymidine. The major cofactors involved in purine and pyrimidine metabolisms that act as oncometabolites are nicotinamide mononucleotide (NMN), nicotinamide adenine dinucleotide (NAD+), nicotinamide adenine dinucleotide phosphate (NADP), dihydrofolate (DHF), and tetrahydrofolate (THF). The abbreviations denote A, Adenine; G, Guanine; U, Uracil; T, Thymine; C5P, Carbamoyl-5-phosphate; UTP, Uridine triphosphate; CTP, Cytidine triphosphate; dCTP, Deoxycytidine triphosphate; dUTP-Deoxyuridine triphosphate; dTMP-Deoxythymidine monophosphate; dTTP, Deoxythymidine triphosphate; Ru5P, Ribulose-5-phosphate; Gln, Glutamine; ATP, Adenosine triphosphate; GTP, Guanosine triphosphate; dATP, Deoxyadenosine triphosphate; and dGTP, Deoxyguanosine triphosphate.

Figure 6

Protein targets influencing oncometabolites for personalized peritoneal cancer therapy. Metabolite inhibitors employed for personalized therapy of peritoneal cancers either as single agent or as component of combinatorial therapy or as an adjuvant are presented. Inhibitors targeting glucose metabolism include inhibitors of hexokinase-2 (HK-2 Inhibitor), glyceraldehyde-6-phosphate dehydrogenase (G6PD Inhibitor), isocitrate dehydrogenase-1 (IDH1 Inhibitor), lactate dehydrogenase (LDH Inhibitor), 6-phosphogluconate dehydrogenase (6PGD Inhibitor), phosphoglycerate kinase-1 (PGK1 Inhibitor), and transketolase, as well as 2-deoxy glucose (2-DG). Inhibitors targeting lipid metabolism include inhibitors of fatty acid translocase CD36 (CD36 Inhibitor), fatty acid binding protein 4 (FABP4 Inhibitor), fatty acid synthase (FASN Inhibitor), acetyl-CoA-carboxylase (ACC Inhibitor), ceramide synthase (CS Inhibitor), and sphingosine kinase I (SPK Inhibitor), and lysophosphatidic acid (LPA Inhibitor). Inhibitors targeting dysregulated amino acid metabolism include inhibitors of glutaminase (GLS Inhibitor), glutamine synthetase (GS Inhibitor), amino acid transporter ASCT-2 (ASCT-2 Inhibitor), glutamate dehydrogenase (GDH Inhibitor), arginase, methionine adenosyl transferase (MAT Inhibitor), and 4-aminobutyrate aminotransferase (ABAT). Inhibitors targeting nucleotide metabolism include inhibitors of dihydrofolate reductase (DHFR), inosine monophosphate dehydrogenase (IMPDH), ribonucleotide reductase (RNR), thymidylate synthase (TS), and folate Inhibitor, as well as nucleoside analogs such as 5-fluorouracil (5-FU) and 2′, 2′-difluoro 2′deoxycytidine or gemcitabine.