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Targeting metabolic vulnerabilities of cancer: Small molecule inhibitors in clinic
Satyendra C Tripathi1, Johannes F Fahrmann1, Jody V Vykoukal1
1Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
Background:
Altered cell metabolism is an established hallmark of cancer. Advancement in our understanding of dysregulated cellular metabolism has aided drastically in identifying metabolic vulnerabilities that can be exploited therapeutically. Indeed, this knowledge has led to the development of a multitude of agents targeting various aspects of tumor metabolism.
Recent Findings:
The intent of this review is to provide insight into small molecule inhibitors that target tumor metabolism and that are currently being explored in active clinical trials as either preventive, stand-alone, or adjuvant therapies for various malignancies. For each inhibitor, we outline the mechanism (s) of action, preclinical/clinical findings, and limitations. Sections are divided into three aspects based on the primary target of the small molecule inhibitor (s): those that impact (1) cancer cells directly, (2) immune cells present in the tumor microenvironment, or (3) both cancer cells and immune cells. We highlight small molecule targeting of metabolic pathways including de novo fatty acid synthesis, NAD+ biosynthesis, 2-hydroxyglutarate biosynthesis, polyamine metabolism, the kynurenine pathway, as well as glutamine and arginine metabolism.
Conclusions:
Use of small molecule inhibitors aimed at exploiting tumor metabolic vulnerabilities continues to be an active area of research. Identifying metabolic dependencies specific to cancer cells and/or constituents of the tumor microenvironment is a viable area of therapeutic intervention that holds considerable clinical potential.
Insights
Small molecule inhibitors targeting cancer cell metabolism are in clinical trials. These agents exploit tumor metabolic vulnerabilities for cancer therapy, showing significant clinical potential.
Area of Science:
- Oncology
- Cancer Metabolism
- Drug Development
Background:
- Altered cellular metabolism is a key characteristic of cancer.
- Understanding cancer metabolism reveals vulnerabilities exploitable for therapy.
- Numerous agents targeting tumor metabolism have been developed.
Purpose of the Study:
- To review small molecule inhibitors targeting tumor metabolism in clinical trials.
- To outline mechanisms, findings, and limitations of these inhibitors.
- To categorize inhibitors based on their impact on cancer cells and/or the tumor microenvironment.
Main Methods:
- Review of small molecule inhibitors in active clinical trials.
- Analysis of inhibitors targeting cancer cells, immune cells, or both.
- Focus on metabolic pathways: fatty acid synthesis, NAD+ biosynthesis, 2-hydroxyglutarate, polyamine, kynurenine, glutamine, and arginine metabolism.
Main Results:
- Small molecule inhibitors targeting tumor metabolism are under active investigation.
- These inhibitors are explored as preventive, stand-alone, or adjuvant therapies.
- Targeted metabolic pathways include de novo fatty acid synthesis, NAD+ biosynthesis, and others.
Conclusions:
- Targeting tumor metabolic vulnerabilities with small molecule inhibitors is a promising research area.
- Identifying cancer-specific metabolic dependencies offers therapeutic potential.
- These strategies hold considerable promise for clinical intervention in malignancies.
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