Clinically-targetable vulnerabilities in cancer metabolism: A systematic review and meta-analysis

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Date: Dec. 31, 2020
From: Journal of Pakistan Medical Association(Vol. 70, Issue 12)
Publisher: Knowledge Bylanes
Document Type: Report
Length: 6,556 words
Lexile Measure: 1760L

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Byline: Arslaan Javaeed and Sanniya Khan Ghauri

Keywords: Metabolic vulnerabilities, Cancer, Chemotherapy, Cell metabolism, Metabolic enzymes.

Introduction

Aberrant metabolic activities in cancer cells have merited the attention of researchers predating the detection of tumour suppressors and oncogenes by approximately 50 years. The knowledge regarding cancer metabolism was initially inspired by Otto Warburg,1 who reported a 10-fold increase in the catabolism of glucose carbon to lactate in tumour cells compared to normal cells even in the existence of oxygen. This metabolic alteration was supposedly attributable to mitochondrial defects that precluded their capacity of glucose carbon oxidation to carbon dioxide.1 As such, 18F-deoxyglucose positron emission tomography (FDG-PET) has been utilised in cancer detection, showing an efficient clinical promise.2

Nonetheless, recent understanding of cancer biology has revealed contradictory observations. The aerobic glycolysis exhibited by tumour cells is not inherently related to mitochondrial dysfunctionality or impaired oxidative phosphorylation, but rather ascribed to a "reprogrammed" mitochondrial metabolism that leads to an increase in the macromolecular synthesis.3 Indeed, reprogramming is a complicated process that can be mediated by mutagenesis or epigenetic modifications in tumour suppressor genes, such as Von Hippel-Lindau tumour suppressor (VHL), retinoblastoma (Rb) and tumour protein 53 (p53), or oncogenes, such as nuclear factor erythroid 2-related factor 2 (NRF2) and the P110[alpha]-encoding gene PIK3CA.4

Furthermore, other cellular factors can influence cancer metabolism, including nutrient limitation, cellular interaction and oxygen availability.4 Moreover, the ability of a given oncogene to change metabolism in a specific tissue but not another has raised the possibility of tissue-specific signalling involvement.5

The variation in metabolic dependencies of cancer cells created a considerable number of metabolic liabilities that could be targeted therapeutically. These therapies exploit vulnerable aspects critical for tumour growth and survival and hence, could be clinically useful. However, metabolomic studies were primarily performed in cancer cell lines rather than the pathogenic tumours,6 demonstrating the potential molecular mechanisms involved in metabolic reprogramming as well as altered signalling pathways. Culture-based experimental models may yield different outcomes when compared to the real oncogenic microenvironment. It is also worthy to note that the metabolic liabilities in some in vivo studies have not been previously reported in their counterparts conducted on culture cells.5

Given that the novel therapeutic strategies against cancer are either in use clinically or being assessed in the preclinical and clinical settings, this systematic review was planned to provide an insight into the most recent knowledge about cancer metabolism and how the therapeutic targets could be approached, focussing on the efficacy and safety of them.

Methods

The systematic review and meta-analysis of studies that investigated a potential metabolic vulnerability to be exploited in any cancer was conducted on Articles in English, published in a peer-reviewed journal and its full version was available. The systematic review relied on a literature search of the exploitable vulnerabilities based on updating and extending a previously-published review.7

The identified clinically-targetable aspects of cancer metabolism included glycolysis, fatty acid metabolism, tricarboxylic acid cycle and mitochondrial metabolism, amino acid metabolism and nucleic acid synthesis. Cohort studies and randomised...

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Gale Document Number: GALE|A645425831