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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...

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Autores principales: Chin, Alexander, Bieberich, Charles J., Stewart, Tracy Murray, Casero, Robert A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9228337/
https://www.ncbi.nlm.nih.gov/pubmed/35736351
http://dx.doi.org/10.3390/medsci10020031
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author Chin, Alexander
Bieberich, Charles J.
Stewart, Tracy Murray
Casero, Robert A.
author_facet Chin, Alexander
Bieberich, Charles J.
Stewart, Tracy Murray
Casero, Robert A.
author_sort Chin, Alexander
collection PubMed
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.
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spelling pubmed-92283372022-06-25 Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses Chin, Alexander Bieberich, Charles J. Stewart, Tracy Murray Casero, Robert A. Med Sci (Basel) Review 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. MDPI 2022-06-10 /pmc/articles/PMC9228337/ /pubmed/35736351 http://dx.doi.org/10.3390/medsci10020031 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Chin, Alexander
Bieberich, Charles J.
Stewart, Tracy Murray
Casero, Robert A.
Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses
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 Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9228337/
https://www.ncbi.nlm.nih.gov/pubmed/35736351
http://dx.doi.org/10.3390/medsci10020031
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