Interactions of IDO and the Kynurenine Pathway with Cell Transduction Systems and Metabolism at the Inflammation–Cancer Interface
Abstract
:Simple Summary
Abstract
1. Introduction
2. IDO and Kynurenine in the Immune System
2.1. IDO and Immunological Tolerance
2.2. T Cell Exhaustion
2.3. Kynurenic and 3-Hydroxyanthranilic Acids
2.4. IDO Modulation and Cancer Susceptibility
2.5. KMO Involvement
3. Kynurenine Pathway Interactions with Transduction Pathways
3.1. AHR
3.2. AHR and Homing
3.3. Programmed Cell Death Protein-1 (PD-1/PD-L1)
3.4. NFκB
3.5. Therapeutic Implications
3.6. Epigenetics and PD-1
3.7. FoxP3
3.8. FOXO1
3.9. miRNA
4. Metabolic Interactions
4.1. Anaerobic Glycolysis
4.2. Glutamine Metabolism
4.3. Miscellaneous Metabolic Factors
4.4. COX and Oxidative Stress
4.5. HIF-1α
4.6. Pyruvate Dehydrogenase Lipoamide Kinase Isozyme 1 (PDK1)
4.7. Status of Drug Development
Compound | Molecular Target | Trial Target and Phase | Trial ID (NCT) | Reference and Comment |
---|---|---|---|---|
Indoximod (1-methyl-D-tryptophan; NLG-8919) | IDO1 activity inhibition; stimulates mTORC to modulate downstream transduction; promotes kynurenate formation | Metastatic breast cancer Phase 2 | NCT02913430 | NLG-802 is a prodrug for this, which entered Phase 1 in 2020 |
Indoximod (1-methyl-D-tryptophan) | As above | Glioblastoma Phase 2 | NCT04049669 | |
Indoximod (1-methyl-D-tryptophan) | As above | Metastatic prostate cancer; Phase 2 | NCT01560923 | [224] Combination with sipuleucel-T yielded radiological and clinical improvement |
Indoximod (1-methyl-D-tryptophan) | As above | Metastatic pancreatic cancer; Phase 2 | NCT02077881 | [225] |
Indoximod (1-methyl-D-tryptophan) | As above | Metastatic breast cancer; Phase 2 | NCT01792050 | [226] No improvement compared with taxane |
Epacadostat INCB024360 | IDO1 inhibitor. IC50 = 93 nM in direct enzyme assay; IC50 = 12.5 nM in HeLa cell-based assay | Prostate cancer; Phase 1 and 2 | NCT 03493945 | [227,228] |
Epacadostat INCB024360 | As above | Gliomas; Phase 2 | NCT03532295 | |
Epacadostat INCB024360 | As above | Endometrial cancer; Phase 2 | NCT04463771 | |
Epacadostat INCB024360 | As above | Head and neck cancer; Phase 2 | NCT03463161 |
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Stone, T.W.; Williams, R.O. Interactions of IDO and the Kynurenine Pathway with Cell Transduction Systems and Metabolism at the Inflammation–Cancer Interface. Cancers 2023, 15, 2895. https://doi.org/10.3390/cancers15112895
Stone TW, Williams RO. Interactions of IDO and the Kynurenine Pathway with Cell Transduction Systems and Metabolism at the Inflammation–Cancer Interface. Cancers. 2023; 15(11):2895. https://doi.org/10.3390/cancers15112895
Chicago/Turabian StyleStone, Trevor W., and Richard O. Williams. 2023. "Interactions of IDO and the Kynurenine Pathway with Cell Transduction Systems and Metabolism at the Inflammation–Cancer Interface" Cancers 15, no. 11: 2895. https://doi.org/10.3390/cancers15112895