Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses

Abstract

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.

Histone deacetylase-10 liberates spermidine to support polyamine homeostasis and tumor cell growth

“…Blocking this restoration of homeostasis is the goal of polyamine-blocking therapies, which incorporate the simultaneous inhibition of biosynthesis and transport ( 23 , 25 , 46 , 47 , 48 ). Several studies have indicated this to be a promising strategy, with effects on tumor cells as well as tumor-associated immune cells ( 14 , 49 ). However, mammalian polyamine transport is complex, and its mechanisms have not been fully elucidated.…”

Pancreatic Cancer Research beyond DNA Mutations

“…A polyamine is an organic compound that has more than two amino groups. Polyamine metabolism is associated with the production of S-adenosylmethionine (SAM), a methyl donor for the methylation of critical substances, such as DNA, RNA, and histones [ 18 ]. Polyamine biosynthesis is frequently upregulated in cancer [ 18 ].…”

“…Polyamine metabolism is associated with the production of S-adenosylmethionine (SAM), a methyl donor for the methylation of critical substances, such as DNA, RNA, and histones [ 18 ]. Polyamine biosynthesis is frequently upregulated in cancer [ 18 ]. The enhanced flux of polyamines and their metabolites increases the levels of intracellular polyamines that are necessary for promoting cell growth and proliferation through intracellular biochemical mechanisms, such as the one-carbon metabolism in mitochondria and cell-to-cell interaction [ 18 ].…”

“…Polyamine biosynthesis is frequently upregulated in cancer [ 18 ]. The enhanced flux of polyamines and their metabolites increases the levels of intracellular polyamines that are necessary for promoting cell growth and proliferation through intracellular biochemical mechanisms, such as the one-carbon metabolism in mitochondria and cell-to-cell interaction [ 18 ]. A previous study on polyamine metabolism analyzed human tissues and PAN 02 murine pancreatic cancer cells orthotopically injected into the pancreas of immune-competent C57Bl/6 mouse; the results revealed that polyamines play a major role in the development of PDAC [ 19 ] and in controlling the tumor microenvironment (TME) [ 20 ].…”

The Involvement of Polyamines Catabolism in the Crosstalk between Neurons and Astrocytes in Neurodegeneration

“…Another important transporter for PAs is the vesicular transporter SLC18B1, present in both neurons and astrocytes [ 14 ], which was found to be involved in regulating the PA content, the function of the GABA and glutamatergic systems, memory, synaptic function and plasticity [ 15 , 16 ]. Recently, the P-type ATPase transporter ATP13A3 has also been demonstrated to be involved in PA mammalian import [ 17 , 18 ]. In the adult brain, neurons are capable of synthetizing PAs [ 4 , 19 , 20 ], and glial cells but not neurons accumulate PAs [ 4 , 21 , 22 , 23 , 24 ].…”