Developing dietary interventions as therapy for cancer

Abstract

Cancer cells acquire distinct metabolic preferences based on their tissue of origin, genetic alterations and degree of interaction with systemic hormones and metabolites. These adaptations support the increased nutrient demand required for increased growth and proliferation. Diet is the major source of nutrients for tumours, yet dietary interventions lack robust evidence and are rarely prescribed by clinicians for the treatment of cancer. Well-controlled diet studies in patients with cancer are rare, and existing studies have been limited by nonspecific enrolment criteria that inappropriately grouped together subjects with disparate tumour and host metabolic profiles. This imprecision may have masked the efficacy of the intervention for appropriate candidates. Here, we review the metabolic alterations and key vulnerabilities that occur across multiple types of cancer. We describe how these vulnerabilities could potentially be targeted using dietary therapies including energy or macronutrient restriction and intermittent fasting regimens. We also discuss recent trials that highlight how dietary strategies may be combined with pharmacological therapies to treat some cancers, potentially ushering a path towards precision nutrition for cancer.

Fig. 1 |. Nutrient utilization in cancer.

Various pathways mediate conversion of extracellular sugars, fats and amino acids into energy or building blocks for anabolic processes. Enzymes critical to and/or frequently upregulated in cancer in these pathways are shown, colour coded according to their primary nutrient association: fructose (beige), glucose (pink), lipid uptake and degradation (yellow) and amino acid metabolism (blue). ACC, acetyl-CoA carboxylase; ACLY, ATP citrate lyase; ACSS, acetyl-CoA synthetase; ALDO, aldolase; ATs, arginine transporters; BCAAs, branched-chain amino acids; BCATs, branched-chain amino acid transaminases; CPT1, carnitine palmitoyl transferase I; FAO, fatty acid oxidation; FASN, fatty acid synthase; G6PD, glucose-6-phosphate dehydrogenase; GLS, glutaminase; GLUT, glucose transporter; GSS, glutathione synthetase; (mt)IDH, (mutated) isocitrate dehydrogenase; KHK, ketohexokinase; LATs, L-type amino acid transporters; LDH, lactate dehydrogenase; LDLR, low-density lipoprotein receptor; MCTs, mono-carboxylase transporters; PDH, pyruvate dehydrogenase; PHGDH, phosphoglycerate dehydrogenase; PKM2, pyruvate kinase isoform M2; PPP, pentose-phosphate pathway; SCD, stearoyl-CoA desaturase; SDH, sorbitol dehydrogenase; SLC1A4, solute carrier family 1 member 4; SLC1A5, solute carrier family 1 member 5; SLC7A11, solute carrier family 7 member 11.

Fig. 2 |. Tissue-specific metabolism.

Notable metabolic features of various tissues. Anatomic location of these tissues as well as metabolic demands of their normal function may impart vulnerabilities that can be targeted with diet and/or pharmacotherapy. See main text for relevant references. BCAAs, branched-chain amino acids; IGF1, insulin-like growth factor 1.

Fig. 3 |. Development progress for dietary interventions for cancer.

Several dietary interventions are advancing well along the clinical development pipeline, with specific example trials highlighted. Based on evidence primarily in subjects with breast cancer, low-fat diet (LFD) is often recommended to patients with cancer^–. Calorie restriction is safe in subjects with cancer, yet a high dropout rate and poor funding have limited formal efficacy studies^,. Very low carbohydrate diet (VLCD) and fasting mimicking diet (FMD) are rapidly advancing through safety and feasibility studies, and efficacy trials are on the horizon in subjects with cancer^,. Time-restricted feeding and diets depleted in specific amino acids have shown efficacy in mouse models, but limited clinical data are available.