Drugging cancer metabolism: Expectations vs. reality

Abstract

As compared to their normal counterparts, neoplastic cells exhibit a variety of metabolic changes that reflect not only genetic and epigenetic defects underlying malignant transformation, but also the nutritional and immunobiological conditions of the tumor microenvironment. Such alterations, including the so-called Warburg effect (an increase in glucose uptake largely feeding anabolic and antioxidant metabolism), have attracted considerable attention as potential targets for the development of novel anticancer therapeutics. However, very few drugs specifically conceived to target bioenergetic cancer metabolism are currently approved by regulatory agencies for use in humans. This reflects the elevated degree of heterogeneity and redundancy in the metabolic circuitries exploited by neoplastic cells from different tumors (even of the same type), as well as the resemblance of such metabolic pathways to those employed by highly proliferating normal cells. Here, we summarize the major metabolic alterations that accompany oncogenesis, the potential of targeting bioenergetic metabolism for cancer therapy, and the obstacles that still prevent the clinical translation of such a promising therapeutic paradigm.

Prognostic Implications of Metabolism Related Gene Signature in Cutaneous Melanoma

“…Altered metabolism is considered to be related to cancer cell survival and growth ( 4 , 18 ). Various metabolisms, such as the glucose and glutamine metabolism of cancer cells, can be significantly changed by tumor microenvironment across an individual tumor ( 19 , 20 ). However, the tumor can also acclimatize itself to metabolic reprogramming, suggesting the specificity of metabolic targets to each cancer ( 20 ).…”

“…Various metabolisms, such as the glucose and glutamine metabolism of cancer cells, can be significantly changed by tumor microenvironment across an individual tumor ( 19 , 20 ). However, the tumor can also acclimatize itself to metabolic reprogramming, suggesting the specificity of metabolic targets to each cancer ( 20 ). Metabolic gene signatures have been shown to have a prognostic role in cancers ( 21 , 22 ).…”

Survival-Associated Metabolic Genes in Human Papillomavirus-Positive Head and Neck Cancers

“…Examination of how the metabolic phenotype differs between HPV+ and HPV-HNSCC could lead to the identification of targetable metabolic changes and potential new treatment options that are specific for either HPV+ HNSCCs or HPV-HNSCCs. Admittedly, cancer metabolism is complex as it impinges on a variety of other cellular processes and can vary across an individual tumour [16]. In addition, tumours can be highly adaptive to metabolic perturbations [16].…”

“…Admittedly, cancer metabolism is complex as it impinges on a variety of other cellular processes and can vary across an individual tumour [16]. In addition, tumours can be highly adaptive to metabolic perturbations [16]. Identifying multiple metabolic targets that are specific to a cancer type from a large dataset that contains information from an extensive number of tumours, such as The Cancer Genome Atlas (TCGA), is an ideal step towards selecting or generating useful anti-metabolic cancer therapeutics.…”

Possible mechanisms of cancer prevention by nicotinamide

“…The anti-acne activity of NAM has been attributed to the suppression of toll-like receptor 2 (TLR2) signalling driven by cutaneous bacteria (Niren, 2006), culminating with decreased secretion of proinflammatory cytokines (Kim et al, 2002;Vanpouille-Box, Hoffmann, & Galluzzi, 2019). In addition, NAM has been repeatedly tested for its ability to synergize with carbogen (95% O 2 and 5% CO 2 ) in improving oxygenation in the tumour micro-environment and hence increasing cancer sensitivity to radiation therapy (RT) (Bernier et al, 1999;Hoskin, Rojas, Saunders, Bentzen, & Motohashi, 2009;Janssens et al, 2012;Miralbell et al, 1999;Rademakers et al, 2015).…”