Arslaan Javaeed  ( Department of Pathology, Poonch Medical College, Azad Kashmir, Pakistan )
Sanniya Khan Ghauri  ( Department of Emergency Medicine, Shifa International Hospital, Islamabad )

Objectives: To investigate the efficacy and safety of targeting cancer metabolic vulnerabilities with specific anticancer agents.

Method: The systematic review and meta-analysis entailed search on PubMed, Embase and Google Scholar databases for cohort-based studies or clinical trials which reported hazard ratio for overall survival and/or median overall survival of patients treated with metabolicallyactive anticancer drugs. Data was analysed using the Number Cruncher Statistical System version 11.

Results: There were 16 studies published between 1989 and 2018 that reported improvement in the overall survival (p=0.05) despite the reported significant heterogeneity across the studies (I2=70%). Exploiting amino acid metabolic vulnerabilities was associated with a favourable prognostic outcome (p=0.05), while targeting glycolysis and nucleic acid synthesis had no significant clinical importance (p>0.05).

Conclusion: There is an urgent need to develop future therapies relying on the synergistic actions of nucleotide biosynthesis, glycolysis and amino acid metabolism.

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

 

DOI: https://doi.org/10.47391/JPMA.079

 

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 P110α-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 tissuespecific 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 clinical trials (RCTs) were included in the systematic review. For meta-analysis, the eligible studies were those which compared survival outcomes in an intervention group with a control group and reported the hazard ratios (HRs) as indicators of patients' survival following the administration of anticancer drugs. HR was used as a marker to analyse survival since this measurement is more preferably employed in meta-analyses over median survival times or survival rates.⁸ Articles excluded were experimental investigations performed on cell cultures, literature reviews, metaanalyses and case reports. Additionally, studies with sample sizes <20 were also excluded. There was no limit for the publication date in the search process.

 

The search process

 

The review was based on the guidelines of the Preferred Reporting Items for Systematic Review and Meta-analysis protocols (PRISMA-P).⁹ As such, the patient (P), intervention (I), control (C) and outcome (O), PICO, framework was used to structure and develop the search strategy according to the Cochran's handbook of systematic reviews of interventions.¹⁰ Databases searched for eligible articles were PubMed, Clinicaltrials.gov, Embase and Google Scholar. Search terms used were: cancer metabolism AND patients, cancer metabolism AND clinical trial, glycolysis AND cancer AND patient, glycolysis AND cancer AND patient, gluconeogenesis AND cancer AND patient, fatty acid metabolism AND cancer AND patient, TCA (tricarboxylic acid) cycle and mitochondrial metabolism AND cancer AND patient, amino acid metabolism AND cancer AND patient and nucleic acid synthesis AND cancer AND patient. Screening of eligible studies was performed through their titles and abstracts until October 2018. The bibliographies of all pertinent articles were searched for available studies to be possibly included.

 

Data collection and extraction

 

Search results were uploaded onto Endnote software (Clarivate Analytics, Philadelphia, United States). Following the screening process, the abstracts and full texts were analysed and eligible articles were included. For the systematic review, retrieved data, including authors' names, year of publication, sample size, study design, metabolic target, mode of action, potential anticancer agent, stage of development, target cancer and HR and/or median overall survival (OS) with a 95% confidence interval (CI) were extracted into a specificallydesigned table. The mode of action of cancer therapy was either expressed as normalisation or depletion, where the former meant causing readjustment of the conversion rates of metabolites toward those occurring in normal metabolic pathways evidently in healthy cells, while the latter indicated inhibition of essential pathways critical for tumour cell growth. Data extraction was performed by two independent researchers and failure to reach a consensus was resolved by either discussion or consulting a third reviewer. When available, the reported HR was collected and integrated for subsequent analysis.

 

Outcomes and test hypothesis

 

The primary outcome was reporting the median OS or HR of OS for an agent that targeted a metabolic vulnerability in cancer cells. Based on an extensive literature search, it was hypothesised that metabolic anticancer agents had significant effect on improving patients' survival.

 

Quality assessment

 

The quality assessment of the included studies was conducted using the Newcastle-Ottawa quality assessment scale¹¹ for cohort and case-control studies. It included a quality assessment of distinct criteria, including selection and comparability of the study groups as well as ascertainment of exposures or outcomes. In such scales, a specific star system is employed where both cohort and case-control studies are assigned a maximum of two stars for the comparability item, while other items can be awarded a maximum of one star for each, yielding a 0-9 range. Low-quality articles were deemed at score 0-3, moderate quality at 4-6 and high quality at 7-9. On the other hand the Jadad score¹² was used to assess the quality of Phase III RCTs according to randomisation and doubleblinding. Such method relies on a score ranging between 0 (bad) and 5 (good), using a 7-item scale, where the last two items deduct a negative score. Phase I/II trials were not assessed for their quality due to lack of relevant scales, yet their results were considered in the qualitative research.

 

Statistical analysis

 

Meta-analysis was performed only on the comparative studies reporting HRs with 95% CIs as indications for the efficacy of targeting the metabolic vulnerabilities. When they were not available, HRs and CIs were calculated from the median survival times using the survival parameter conversion tool, which is integrated into the Number Cruncher Statistical System version 11 (NCSS 11) statistical software (NCSS, LLC, Utah, US). The pooled effect of relevant therapies on OS was calculated using the Review Manager (RevMan) 5.3 software (The Cochrane Collaboration, Oxford, United Kingdom). The Q test and the I-squared test were used to measure heterogeneity between studies, where a statisticallysignificant heterogeneity was deemed at p<0.05 or I2>50%. In the latter instance, the random effect model was applied.

 

Results

 

Initially, the search yielded 2,754 articles retrieved from the different databases with an additional five studies identified from the bibliographies of the screened articles. Of them, 36(1.3%) studies were assessed for inclusion and 28(78%) of them were included in the systematic review, while 16(44.4%) were considered for the meta-analysis (Figure-1).

A summary was generated of the included studies that investigated the survival data of patients treated with drugs acting on the metabolic vulnerabilities These studies were published between 1989 and 2018 (Tables 1- 3).

Regarding study design, 5(18%) articles were retrospective cohort studies,^13-17 8(28.5%) were phase I/II trials,^18-25 and 15(53.5%)were randomised phase III trials. The authors in 11(39.3%) studies used the anticancer agent as a single therapy,^13-15,23-30 while it was combined with radiotherapy in 6(21.4%) studies^{17,21,22,31-33} and with other chemotherapeutic drugs in the remaining 11(39.3%) studies. For quality assessment, the scores of nonrandomised studies ranged 6-7, indicating a moderate to high quality. The inability to demonstrate the lack of outcomes at the start of the study was inconsistently reported in cohort studies, while the lack of reporting non-response rates was the deficient item in case-control studies (Table-4).

Most of the RCTs scored 3 since only one study employed a double-blinding methodology.³¹ Lower scores were attributable to either the lack of reporting the method of randomisation^32,34 or inappropriate methods of randomisation³⁵ (Table-5).

In general, in the five clinically-targetable aspects of cancer metabolism, there was a significant heterogeneity (P for heterogeneity [Ph]<0.001; I2=70%) and the overall effect tended to improve patients' survival (HR: 0.87; 95% CI: 0.76-1.00; p=0.05; Figure-2).

 

Glycolysis

 

Disruption of glycolysis could be performed via several agents. Lonidamine (LND) is an established inhibitor of the hexokinase (HK) II enzyme, which is involved in the conversion of glucose to glucose-6-phosphate (G6P) as the first step in glycolysis following glucose entry, thereby preserving energy consumption within tumour cells.³⁶ LND was used in combination with other anticancer therapies in all studies, showing OS improvement in breast cancer²⁰ and solid malignant tumours.^18,19 However, targeting HKII by LND in RCTs showed no significant prolongation of the OS compared to the methotrexate-doxorubicin-cyclophosphamide-- lomustine (CCNU) therapy (MACC)³⁷ or radiation therapies.^31,32 Furthermore, subsequent phase clinical trials on benign prostatic hyperplasia were discontinued as a result of the lack of adequate therapeutic efficacy or the development of severe side effects (Clinicaltrials.gov identifiers: NCT00435448, NCT00237536). Given the difference in the outcomes, the present meta-analysis revealed no significant therapeutic effect of targeting glycolysis using LND and the included studies showed a significant heterogeneity (HR: 1.00; 95% CI: 0.73-1.39; p=0.98; Ph: 0.06; I2=65%; Figure-3A).

Also, 2-deoxyglucose (2-DG) is another glucose analogue that is phosphorylated by HKII. The phosphorylated form of 2-DG accumulates in the cells as it is not affected by G6P, thereby glycolysis is halted.³⁸ Oral 2-DG administration was well-tolerated in patients with brain tumours at doses up to 250mg/kg bodyweight (BW) when combined with radiation therapies,^21,22 while the optimum dose of 2-DG in advanced solid tumours was determined at 45mg/kg since higher doses caused asymptomatic prolongation of corrected QT interval (QTc).³⁹ However, the efficacy of such an agent as a therapeutic approach was questionable.⁴⁰ For potential cancerous vulnerabilities under investigation, a Phase I dose-escalating trial showed a lack of dose-limiting toxicity of 6-phosphofructo-2-kinase-158 (PFK-158), which is a potent inhibitor of PFK/fructose 2,6- bisphosphatase (PFKFB3), rendering this agent as the first PFKFB3 inhibitor in human (Clinicaltrials.gov identifier: NCT02044861). TLN-232 is another essential regulatory agent of glycolysis, via inhibition of pyruvate kinase M2, that has been investigated in a Phase II clinical trial in patients having refractory metastatic melanoma (Clinicaltrials.gov identifier: NCT00735332). However, the study was terminated due to the termination of the manufacturer's license.

 

Fatty acid metabolism

 

For drugs affecting cancer metabolism, only statins have been successfully identified as reducing the risk of cancer,⁴¹ possibly by inhibiting hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase that leads to a potent growth inhibition effect on cancer cells.⁴² However, largesized retrospective cohort studies have shown a significant impact on OS in patients with ovarian and breast cancer, with a more prominent role of simvastatin when compared to other drugs.^13,14 Other aspects of lipid metabolic weaknesses of cancer cells are still being investigated in clinical trials. Fatty acid synthase (FAS) is a targetable enzyme involved in the production of membrane phospholipids essential for cancer cell membranes.⁴³ Epigallocatechin gallate (EGCG) is a FAS inhibitor that showed high tolerability, causing a sustained reduction of the absolute lymphocytic count in 69% of patients with Rai stage I to II chronic lymphocytic leukaemia (n=42).⁴⁴ TVB-2640 is another FAS inhibitor which is currently under investigation on three different types of cancer, while only one clinical trial was being held on a novel choline kinase alpha (Chk-α) inhibitor named traslational cancer drug (TCD)-717.^45-47

 

TCA cycle and mitochondrial metabolism

 

Given that mitochondrial metabolism in cancer cells is not only dependent on glucose-derived pyruvate but also on fatty acids, lactate and amino acids, such as glutamine, to supply carbon sources for the TCA cycle,⁴⁸ multiple metabolic weaknesses could be targeted in these pathways. Dichloroacetate (DCA) has completed a Phase I trial in 8 patients with recurrent malignant brain tumours and was not associated with dose-limiting toxicities,²³ yet further investigations were not performed. Interestingly, a new era of acute myeloid leukaemia (AML) treatment has emerged with the introduction of two recently-approved agents that induce glutaminolysis in AML patients. Ivosidenib (AG-120) has been approved at a dose of 500mg daily, showing an overall response in 41.6% patients (95% CI: 32.9-50.8) with a low frequency of grade 3 or higher adverse effects in patients with mutant isocitrate dehydrogenase (IDH)-1 mutant AML.²⁴ Targeting the mutant IDH-2 enzyme by the potent inhibitor enasidenib (AG-221) was also evaluated in a Phase I escalation trial²⁵ with an overall response rate of 40.3% and a significant hematologic response. Metformin is another antidiabetes agent that could be assessed for its metabolically-active role in cancer. Nonetheless, observational studies⁴⁹ and large-base prospective investigations⁵⁰ have revealed that the impact of metformin was only limited to reducing the risk of cancer in patients with type 2 diabetes, or reducing the overall mortality in diabetic metformin-receiving patients compared to non-diabetic individuals (HR: 0.85; 95% CI: 0.78-0.93).¹⁵ For the ongoing trials, the therapeutic effects of CB-839 are being investigated in multiple types of cancer after inducing reversible side effects (elevation of transaminases) at doses ranging between 100 and 1000mg ter in die (TID), or three times a day, in patients with relapsed/refractory leukaemia.⁵¹ Lactate utilisation by tumour cells might also be regarded as a therapeutically-liable vulnerability that is being approached clinically by the monocarboxylate transporter inhibitor AZD3965 (Clinicaltrials.gov identifier: NCT01791595).

 

Amino acid metabolism

 

L-asparaginase has been approved in the standard regimen of acute lymphoblastic leukaemia (ALL) and related lymphoma as it depletes asparagine necessary for cancer cells. The effects of such therapy were likely to be more favourable in children with ALL rather than the adolescent and adult populations, where adverse side effects, such as pancreatitis, hypersensitivity reaction and thrombosis, have been frequently reported.^16,34,52 Arginine is another amino acid that could be available for cancer cells and hence, therapies that deplete exogenous arginine may be effective, particularly in argininosuccinate synthetase-1 (ASS-1)-deficient cancers.⁵³ The use of pegylated arginine deiminase (ADIPEG20) has yielded a remarkable improvement in progress-free survival (PFS) in patients with ASS-1- deficient pleural mesothelioma (HR: 0.56; 95% CI: 0.33- 0.96; p=0.02).⁵⁴ Another possible mechanism that could be exploited in cancer metabolism is the inhibition by difluoromethylornithine (DFMO) of ornithine decarboxylase, which leads to increased polyamine levels and tumorigenesis,. Although Saulnier Sholler et al.⁵⁵ have shown that children with polyamine-dependent relapsed neuroblastoma are susceptible to DFMO with remarkable safety and tolerability, two RCTs have revealed no survival benefits of adding DFMO with procarbazine-lomustine-vincristine (PCV) therapy in patients with glioblastoma and astrocytoma.^56,57 Overall, the included studies that targeted amino acid metabolism had the most favourable effect estimates on OS as indicated by a pooled HR of 0.67 (95% CI: 0.45-1.00; p=0.05). However, these results should be cautiously interpreted given the significant inconsistency between the included studies (Ph<0.01; I2=84%; Figure-3B).

 

Nucleic acid synthesis

 

Gemcitabine is an antimetabolite nucleoside analogue that inhibits deoxyribonucleic acid (DNA) polymerase and thus, can be used to treat cancer. The survival outcomes of this agent were conflicting. Four RCTs investigated the use of a single gemcitabine therapy, showing an additional survival benefit rather than observation following pancreatic cancer resection^27,28 but not following bile duct cancer resection.²⁶ Furthermore, patients with pancreatic malignancies who received a folinic acid-fluorouracil-irinotecan-oxaliplatin (FOLFIRINOX) therapy showed better survival outcomes when compared to those who received gemcitabine.²⁹ Similarly, the impact of 5-fluorouracil (5-FU) on exploiting cancer metabolic vulnerabilities through the inhibition of DNA synthesis was inconsistent in the RCTs. While 5-FU administration yielded a significant increase in the five-year survival rate after pancreatic cancer resection when compared to a combination of 5-FU and radiotherapy (21% versus 8%, respectively; p=0.009),³⁰ there was no significant beneficial effects of adjuvant chemotherapies containing 5-FU, alpha interferon and interleukin-2 (IL-2) or 5-FU and capecitabine following nephrectomy for renal cell carcinoma mesorectal excision for rectal cancer, respectively.^33,58 As such, drugs that target nucleic acid synthesis showed no significant effect on patients' survival as an indication of targeting the metabolic cancer weaknesses (HR: 0.93; 95% CI: 0.78-1.12; p=0.93; Figure-3C).

 

Discussion

 

Several metabolic vulnerabilities have been successfully exploited in cancer cells, showing varied efficacy degrees, but their use may be limited by their toxicities rather than by their cancer cell-killing capabilities. The present study reviewed the possible clinically-exploited weaknesses and investigated the effects of targeted therapies through their HRs to compare their efficacy, tolerability and patients' prognosis. The most commonly investigated targetable changes were glycolysis, glutaminolysis and nucleic acid synthesis. Our results emphasised the significance of targeting amino acid metabolism. Cancer cells show an increased demand for distinct amino acids that might be considered a "metabolic addiction". Such characteristics involve increased nitrogen requirements for biosynthesis, increased amino acid consumption and elevation of their relevant transporters, increased dependence on exogenous non-essential amino acids that exceeds the capacity of intracellular supply and altering the levels of amino acid-specific catalytic enzymes.⁵⁹ Bu et al.¹⁷ found that a combination of L-asparaginase and radiotherapy was associated with a remarkably increased OS compared to a cyclophosphamide- hydroxydaunorubicinvincristine- prednisone (CHOP) regimen in patients with extranodal natural killer cell/T-cell lymphoma (77 versus 34 months, respectively; p<0.001). The present systematic review showed that targeting glucose uptake at the early steps of glycolysis was not efficacious. This could be explained by the fact that glucose uptake is also enhanced in non-cancerous tissue, including the brain, as shown by FDG-PET scans,⁶⁰ indicating that glucose uptake is not a unique property of cancer cells. As such, direct targeting of such vulnerability may be limited by the synergistic effects that may be exerted by 2-DG therapies on normal cells. However, efforts in the preclinical studies are still ongoing to exploit other aspects of glycolysis, such as the use of glucose transporter (GLUT) inhibitors (WZB117 and Fasentin) for clinical use.⁶¹ Moreover, Cervantes-Madrid et al.⁶² have reasonably suggested the renewal of the LND-concerned studies, particularly when it is combined with 6-diazo-5- oxo-L-norleucine (DON) to target glycolysis and glutaminolysis, respectively. Importantly, targeting the enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) by 3-bromopyruvate (3-BrPA) is possible, providing an energy-depleting approach specific to cancer cells. The clinical success of targeting nucleic acid synthesis was variable in the included RCTs in the present study. Although the increased metabolic demand of cancer cells to DNA replication and nucleotide synthesis is crucial, the concomitant destruction of other highly proliferative normal cells in the body, including intestinal crypts, hair follicles and bone marrow, may limit the overall effects of antimetabolites that may be associated with doselimiting toxicities, such as myeloid suppression and gastrointestinal toxicities.⁶³ Gemcitabine was efficient as a single therapy although its efficacy was inferior to the FOLFIRINOX therapy. Its cytotoxic effect showed a potent synergism with cisplatin and such combination may be regarded as the first-line treatment of nasopharyngeal carcinoma.⁶⁴ Moreover, the adjuvant combination of capecitabine and gemcitabine was superior to gemcitabine alone as a post-surgical therapy for pancreatic ductal carcinoma.⁶⁵ However, intrinsic or acquired gemcitabine resistance has been reported in pancreatic cancer elsewhere,⁶⁶ and recent preclinical evidence has revealed that such resistant cells could be sensitised by disruption of the glutamine pathways via an adjuvant DON therapy.⁶⁷ The synergistic action of antimetabolite drugs and glutaminolytic drugs could be explained by the interference of nucleotide biosynthesis with other metabolic pathways, where glucose requirements for ribose synthesis are derived from the pentose-phosphate pathway while aspartate and glutamine provide the required nitrogen atoms for nucleotide bases. Indeed, these essential synergistic actions would potentially widen the therapeutic solutions. Considering mitochondrial metabolism, the present review highlighted the clinical importance of two novel agents against relapsed/refractory AML that target mutant IDH isoforms without inducing significant bone marrow aplasia. More specifically, the prolonged OS of enasidenib in elderly patients with advanced myeloid malignancies was remarkable and comparable with shorter survival outcomes in a randomised Phase 1/2 study.⁶⁸ From another perspective, new horizons in cancer metabolism could be elucidated by targeting fatty acid synthesis since the current confirmed evidence is scarce and only limited to statins. For example, Penet et al.⁶⁹ recommended evaluating TCD-717 as a Chk-α inhibitor in the treatment of pancreatic cancer cells as they usually express impaired choline metabolism. The ongoing clinical trials could provide a better insight into the prospected clinical effectiveness. Targeting the metabolic vulnerabilities would possibly open new therapeutic windows, particularly in light of the need to reduce enzyme-mediated resistance to chemotherapeutic agents, including paclitaxel resistance in breast cancer,⁷⁰ hypoxia-induced resistance in solid tumours,⁷¹ and cisplatin resistance in gastric cancer.⁷² Observational and retrospective studies were excluded from our meta-analysis to yield more reliable outcomes and to avoid significant time-related biases. However, this study may have some limitations. First, the available clinical data is still insufficient to conclude a robust approach for further investigations in cancer metabolism despite the significance of amino acid metabolism. Second, determining HR as a primary outcome in the present study might lead to reducing the number of included studies and thereby some articles may have escaped inclusion. Third, the significant inconsistencies among the included studies in our meta-analysis, possibly due to variation in the combined therapies and control groups, might render a difficult interpretation.

 

Conclusion

 

Current evidence has shown that metabolically-active drugs tend to improve OS of patients with solid tumours with a relatively greater effect via exploiting changes in amino acid metabolism. L-asparaginase and ADI-PEG20 are the most acceptable anticancer agents that could be used for the treatment of paediatric and adult ALL and ASS1-negative cancers, respectively. However, combining chemotherapeutic regimens that target the dysregulated metabolic aspects seems to induce better outcomes in terms of efficacy and safety. Given the interfering pathways in nucleotide biosynthesis with glycolysis, folate metabolism and amino acid metabolism, future synergistic therapies should be developed, investigated in preclinical models and employed in the clinical setting as appropriate. Finally, the development of novel cancertargeted therapies based on tumour metabolism is mainly dependent on conducting feasible in vivo studies, utilising advanced imaging techniques and testing potent, selective inhibitors that can be safely introduced to the patients.

 

Disclaimer: None.

Conflict of Interest: None.

Source of Funding: None.

 

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