Dual targeting of polyamine synthesis and uptake in diffuse intrinsic pontine gliomas

Khan, Aaminah; Gamble, Laura D.; Upton, Dannielle; Ung, Caitlin; Yu, Denise; Ehteda, Anahid; Pandher, Ruby; Mayoh, Chelsea; Hebert, Steven C.; Jabado, Nada; Kleinman, Claudia L.; Burns, Mark R.; Norris, Murray D.; Haber, Michelle; Tsoli, Maria; Ziegler, David S.

doi:10.1038/s41467-021-20896-z

Cited by 77 publications

(56 citation statements)

References 54 publications

(73 reference statements)

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“…Recently, Khan et al demonstrated that polyamine synthesis is upregulated in DIPG and, therefore, could be targeted through a synthetic lethality-based approach using a polyamine synthesis inhibitor, difluoromethylornithine (DFMO). Since DIPG cells preferentially escape DFMO inhibition through upregulation of the polyamine transporter SLC3A2, adding polyamine transport inhibitors (AMXT 1501) potentiated tumor-selective cytotoxicity in vitro and in orthotopic animal models [ 55 ]. Additionally, mitochondrial dysfunction has also been implicated in pediatric high-grade gliomas.…”

Section: Pathogenesis: Stem Cell and Mutationmentioning

confidence: 99%

New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of H3K27M-Mutant Diffuse Midline Glioma

Argersinger

Rivas

Shah

et al. 2021

Cancers

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H3K27M-mutant diffuse midline gliomas (DMGs) are rare childhood central nervous system tumors that carry a dismal prognosis. Thus, innovative treatment approaches are greatly needed to improve clinical outcomes for these patients. Here, we discuss current trends in research of H3K27M-mutant diffuse midline glioma. This review highlights new developments of molecular pathophysiology for these tumors, as they relate to epigenetics and therapeutic targeting. We focus our discussion on combinatorial therapies addressing the inherent complexity of treating H3K27M-mutant diffuse midline gliomas and incorporating recent advances in immunotherapy, molecular biology, genetics, radiation, and stereotaxic surgical diagnostics.

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Section: Pathogenesis: Stem Cell and Mutationmentioning

confidence: 99%

New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of H3K27M-Mutant Diffuse Midline Glioma

Argersinger

Rivas

Shah

et al. 2021

Cancers

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“…Arginine metabolism is considered to be an important regulator in controlling immune response ( 48 , 49 ), inhibiting antitumor immune response ( 50 , 51 ), and promoting tumor development ( 34 , 52 ). Ornithine is decarboxylated by ODC1 to produce putrescine, which is the rate-limiting step in polyamine biosynthesis ( 53 , 54 ). Combined with cellular proliferation results ( Figures 7A–D ), we speculate that inhibiting arginine-ornithine metabolism can reduce ornithine content, thus decrease polyamine biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

Acupuncture Synergized With Bortezomib Improves Survival of Multiple Myeloma Mice via Decreasing Metabolic Ornithine

Qian

Feng

et al. 2021

Front. Oncol.

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Multiple myeloma (MM) is a hematological malignancy worldwide in urgent need for novel therapeutic strategies. Since Velcade (bortezomib) was approved for the treatment of relapsed/refractory MM in 2003, we have seen considerable improvement in extending MM patient survival. However, most patients are fraught with high recurrence rate and incurability. Acupuncture is known for alleviating patient symptoms and improving the quality of life, but it is not well investigated in MM, especially in combination with bortezomib. In this study, we employed LC-MS and UHPLC-MS together with bioinformatics methods to test serum samples from 5TMM3VT MM murine model mice with four different treatments [control (C) group, bortezomib (V) treatment group, acupuncture (A) group, and combined (VA) group]. MM mice in group VA had longer survival time than mice in group A or group V. Joint pathway analysis indicated the underlying arginine and proline metabolism pathway among the 32 significantly decreased metabolites in group VA. CCK-8 assay and in vivo experiments validated that ornithine, the metabolite of arginine, promoted MM cell proliferation. In addition, gene expression omnibus (GEO) database analysis suggested that MM patients with higher ornithine decarboxylase 1 (ODC1) expression were evidently associated with poor overall survival. In summary, this study demonstrates the synergistic effects of acupuncture and bortezomib on extending the survival of MM model mice and provides potential therapeutic targets in the treatment of MM.

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“…In this study, we identified worse survival across cancer types in tumors with high combined PA pathway scores suggesting that polyamine synthesis and transport blockade may benefit cancer patients in a T cell-dependent manner. Polyamine blockade therapy (AMXT1501/DFMO) using difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, and AMXT 1501, 28 58 a polyamine transport inhibitor, demonstrates excellent responses in preclinical models of diffuse intrinsic pontine glioma 59 or MYCN transgenic mice. 28 AMXT1501/DFMO shows activity in immunocompetent, but not immunodeficient mouse tumor models.…”

Section: Discussionmentioning

confidence: 99%

Interrogation of T Cell-Enriched Tumors Reveals Prognostic and Immunotherapeutic Implications of Polyamine Metabolism

Harbison

Pandey

Considine

et al. 2021

Preprint

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Background: The presence of cytotoxic tumor infiltrating lymphocytes (TILs) and antigen (e.g., viral, tumor neoantigens) enhances anti-tumor immunity. However, features including recruitment of tolerogenic cell types, nutrient-depletion, and the establishment of an acidic and hypoxic microenvironment diminish anti-tumor lymphocyte function. We sought to understand why the anti-tumor immune response fails despite a favorable immune profile. Methods: We leveraged human papillomavirus-related (HPV+) head and neck squamous cell carcinomas (HNSC) to address this question given their high degree of CD8+ T cell-infiltration and virus-derived tumor-associated antigens. We evaluated expression of 2,520 metabolic genes between HPV+ HNSCs of different prognostic phenotypes. We further tested tumor-intrinsic and -extrinsic sources of polyamine (PA) gene expression based on observations from the prior analysis. We used bulk RNAseq from The Cancer Genome Atlas (TCGA; 10 different cancers) and single cell (sc) RNAseq data from two atlases to parse immune cell contributions to polyamine gene expression. We used TCGA data and an immunotherapy-treated melanoma cohort to examine survival outcomes as a function of polyamine gene set expression. Results: PA metabolism genes were upregulated in aggressive phenotype, T cell-enriched (Thi), HPV+ HNSCs. PA synthesis and transporter gene enrichment was associated with T cell infiltration, recurrent or persistent cancer, overall survival status, primary site, molecular subtype, and MYC genomic alterations. PA synthesis and transport gene sets were more highly expressed in HPV- compared to HPV+ HNSCs. Bulk and scRNAseq data from HPV+ HNSCs demonstrated greater PA catabolism gene set expression among myeloid cells. A combined PA gene set comprised of genes involved in PA synthesis and transport was negatively correlated with cytotoxic T cell functional score across TCGA tumor types. Combined PA gene set expression was associated with greater mortality risk across five tumor types and worse survival in T cell-infiltrated, anti-PD-1-treated melanomas. Conclusions: A genomic approach leveraging T cell-infiltrated, immunogenic HPV+ HNSCs revealed an association between polyamine metabolism, anti-tumor immunity, and prognosis across several cancer types. These data address hurdles to anti-tumor immunity and immunotherapy and warrant further investigation of polyamines as a biomarker for targeted therapy in the context of a T cell-infiltrated microenvironment.

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Dual targeting of polyamine synthesis and uptake in diffuse intrinsic pontine gliomas

Cited by 77 publications

References 54 publications

New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of H3K27M-Mutant Diffuse Midline Glioma

New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of H3K27M-Mutant Diffuse Midline Glioma

Acupuncture Synergized With Bortezomib Improves Survival of Multiple Myeloma Mice via Decreasing Metabolic Ornithine

Interrogation of T Cell-Enriched Tumors Reveals Prognostic and Immunotherapeutic Implications of Polyamine Metabolism

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