Drug discovery strategies in the field of tumor energy metabolism: Limitations by metabolic flexibility and metabolic resistance to chemotherapy
Open accessAbstract
The search for new drugs capable of blocking the metabolic vulnerabilities of human tumors has now entered the clinical evaluation stage, but several projects already failed in phase I or phase II. In particular, very promising in vitro studies could not be translated in vivo at preclinical stage and beyond. This was the case for most glycolysis inhibitors that demonstrated systemic toxicity. A more recent example is the inhibition of glutamine catabolism in lung adenocarcinoma that failed in vivo despite a strong addiction of several cancer cell lines to glutamine in vitro. Such contradictory findings raised several questions concerning the optimization of drug discovery strategies in the field of cancer metabolism. For instance, the cell culture models in 2D or 3D might already show strong limitations to mimic the tumor micro- and macro-environment. The microenvironment of tumors is composed of cancer cells of variegated metabolic profiles, supporting local metabolic exchanges and symbiosis, but also of immune cells and stroma that further interact with and reshape cancer cell metabolism. The macroenvironment includes the different tissues of the organism, capable of exchanging signals and fueling the tumor 'a distance'. Moreover, most metabolic targets were identified from their increased expression in tumor transcriptomic studies, or from targeted analyses looking at the metabolic impact of particular oncogenes or tumor suppressors on selected metabolic pathways. Still, very few targets were identified from in vivo analyses of tumor metabolism in patients because such studies are difficult and adequate imaging methods are only currently being developed for that purpose. For instance, perfusion of patients with [13 C]-glucose allows deciphering the metabolomics of tumors and opens a new area in the search for effective targets. Metabolic imaging with positron emission tomography and other techniques that do not involve [13 C] can also be used to evaluate tumor metabolism and to follow the efficiency of a treatment at a preclinical or clinical stage. Relevant descriptors of tumor metabolism are now required to better stratify patients for the development of personalized metabolic medicine. In this review, we discuss the current limitations in basic research and drug discovery in the field of cancer metabolism to foster the need for more clinically relevant target identification and validation. We discuss the design of adapted drug screening assays and compound efficacy evaluation methods for the discovery of innovative anti-cancer therapeutic approaches at the level of tumor energetics. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.
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The use of isotope labeling to determine metabolic flux and substrate preference is a common practice.
“The use of isotope labeling to determine metabolic flux and substrate preference is a common practice”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [319]
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- Authors
- Amoedo, N. D., Obre, E., & Rossignol, R.
- Affiliations
- Université de Bordeaux (FR)
- Corresponding author
- Rossignol, R.
- ORCID
- Rossignol, R.
- Venue
- Biochimica et Biophysica Acta (BBA) - Bioenergetics
- Publisher
- Elsevier BV
- Published
- 2017-08
- Volume
- 1858
- Issue
- 8
- Pages
- 674-685
- ISSN
- 0005-2728 (ISSN-L)
- OpenAlex
- W2587770349
- Cited by
- 76
- References
- 75
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 6 · 2023: 4 · 2022: 5 · 2021: 15 · 2020: 13 · 2019: 14 · 2018: 10 · 2017: 4
- FWCI
- 1.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Bioenergetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Plan Cancer (BIO2004-06)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- tumor energy metabolism, cancer metabolism, drug discovery, metabolic flexibility, glycolysis inhibitors, glutamine catabolism, lung adenocarcinoma, tumor microenvironment, cancer metabolomics, metabolic imaging, positron emission tomography, drug screening assay, translational failure
- MeSH terms
- Animals, Antineoplastic Agents, Clinical Trials as Topic, Drug Screening Assays, Antitumor, Energy Metabolism, Humans, Mice, Transgenic, Mitochondria, Neoplasms, Oxidation-Reduction, Tumor Cells, Cultured, Mice, Knockout, Drug Resistance, Neoplasm, Mice, Metabolic Networks and Pathways, Metabolomics, Metabolome, Drug Discovery, Molecular Targeted Therapy
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