Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses
Polyamine biosynthesis is frequently dysregulated in cancers, and enhanced flux increases intracellular polyamines necessary for promoting cell growth, proliferation, and function. Polyamine depletion strategies demonstrate efficacy in reducing tumor growth and increasing survival in animal models o...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-06-01
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| Series: | Medical Sciences |
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| Online Access: | https://www.mdpi.com/2076-3271/10/2/31 |
| _version_ | 1797484568708644864 |
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| author | Alexander Chin Charles J. Bieberich Tracy Murray Stewart Robert A. Casero |
| author_facet | Alexander Chin Charles J. Bieberich Tracy Murray Stewart Robert A. Casero |
| author_sort | Alexander Chin |
| collection | DOAJ |
| description | Polyamine biosynthesis is frequently dysregulated in cancers, and enhanced flux increases intracellular polyamines necessary for promoting cell growth, proliferation, and function. Polyamine depletion strategies demonstrate efficacy in reducing tumor growth and increasing survival in animal models of cancer; however, mechanistically, the cell-intrinsic and cell-extrinsic alterations within the tumor microenvironment underlying positive treatment outcomes are not well understood. Recently, investigators have demonstrated that co-targeting polyamine biosynthesis and transport alters the immune landscape. Although the polyamine synthesis-targeting drug 2-difluoromethylornithine (DFMO) is well tolerated in humans and is FDA-approved for African trypanosomiasis, its clinical benefit in treating established cancers has not yet been fully realized; however, combination therapies targeting compensatory mechanisms have shown tolerability and efficacy in animal models and are currently being tested in clinical trials. As demonstrated in pre-clinical models, polyamine blocking therapy (PBT) reduces immunosuppression in the tumor microenvironment and enhances the therapeutic efficacy of immune checkpoint blockade (ICB). Thus, DFMO may sensitize tumors to other therapeutics, including immunotherapies and chemotherapies. |
| first_indexed | 2024-03-09T23:06:15Z |
| format | Article |
| id | doaj.art-cd6982c775e74953aaa7b6580f863085 |
| institution | Directory Open Access Journal |
| issn | 2076-3271 |
| language | English |
| last_indexed | 2024-03-09T23:06:15Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Medical Sciences |
| spelling | doaj.art-cd6982c775e74953aaa7b6580f8630852023-11-23T17:53:37ZengMDPI AGMedical Sciences2076-32712022-06-011023110.3390/medsci10020031Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor ResponsesAlexander Chin0Charles J. Bieberich1Tracy Murray Stewart2Robert A. Casero3Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, MD 21250, USADepartment of Biological Sciences, University of Maryland, Baltimore County, Baltimore, MD 21250, USADepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USADepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USAPolyamine biosynthesis is frequently dysregulated in cancers, and enhanced flux increases intracellular polyamines necessary for promoting cell growth, proliferation, and function. Polyamine depletion strategies demonstrate efficacy in reducing tumor growth and increasing survival in animal models of cancer; however, mechanistically, the cell-intrinsic and cell-extrinsic alterations within the tumor microenvironment underlying positive treatment outcomes are not well understood. Recently, investigators have demonstrated that co-targeting polyamine biosynthesis and transport alters the immune landscape. Although the polyamine synthesis-targeting drug 2-difluoromethylornithine (DFMO) is well tolerated in humans and is FDA-approved for African trypanosomiasis, its clinical benefit in treating established cancers has not yet been fully realized; however, combination therapies targeting compensatory mechanisms have shown tolerability and efficacy in animal models and are currently being tested in clinical trials. As demonstrated in pre-clinical models, polyamine blocking therapy (PBT) reduces immunosuppression in the tumor microenvironment and enhances the therapeutic efficacy of immune checkpoint blockade (ICB). Thus, DFMO may sensitize tumors to other therapeutics, including immunotherapies and chemotherapies.https://www.mdpi.com/2076-3271/10/2/31polyaminestumor microenvironmentcancer therapeuticimmune regulationdifluoromethylornithinepolyamine blocking therapy |
| spellingShingle | Alexander Chin Charles J. Bieberich Tracy Murray Stewart Robert A. Casero Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses Medical Sciences polyamines tumor microenvironment cancer therapeutic immune regulation difluoromethylornithine polyamine blocking therapy |
| title | Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses |
| title_full | Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses |
| title_fullStr | Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses |
| title_full_unstemmed | Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses |
| title_short | Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses |
| title_sort | polyamine depletion strategies in cancer remodeling the tumor immune microenvironment to enhance anti tumor responses |
| topic | polyamines tumor microenvironment cancer therapeutic immune regulation difluoromethylornithine polyamine blocking therapy |
| url | https://www.mdpi.com/2076-3271/10/2/31 |
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