1. Dual targeting of polyamine synthesis and uptake in diffuse intrinsic pontine gliomas
- Author
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Chelsea Mayoh, Mark R. Burns, Ruby Pandher, Anahid Ehteda, Michelle Haber, Laura D. Gamble, David S. Ziegler, Caitlin Ung, Dannielle Upton, Nada Jabado, Claudia L. Kleinman, Maria Tsoli, Steven Hébert, Denise M. T. Yu, Murray D. Norris, and Aaminah Khan
- Subjects
DNA Replication ,0301 basic medicine ,Eflornithine ,Science ,Mice, Nude ,General Physics and Astronomy ,Ornithine Decarboxylase ,Mitochondrial Membrane Transport Proteins ,Article ,General Biochemistry, Genetics and Molecular Biology ,Ornithine decarboxylase ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,Cell Line, Tumor ,Polyamines ,Animals ,Brain Stem Neoplasms ,Humans ,Cell Proliferation ,Dicarboxylic Acid Transporters ,Mice, Inbred BALB C ,Multidisciplinary ,Cell Death ,Chemistry ,Cell growth ,Diffuse Intrinsic Pontine Glioma ,Biological Transport ,Transporter ,Translation (biology) ,General Chemistry ,In vitro ,Gene Expression Regulation, Neoplastic ,CNS cancer ,Disease Models, Animal ,030104 developmental biology ,Preclinical research ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Polyamine - Abstract
Diffuse intrinsic pontine glioma (DIPG) is an incurable malignant childhood brain tumor, with no active systemic therapies and a 5-year survival of less than 1%. Polyamines are small organic polycations that are essential for DNA replication, translation and cell proliferation. Ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme in polyamine synthesis, is irreversibly inhibited by difluoromethylornithine (DFMO). Herein we show that polyamine synthesis is upregulated in DIPG, leading to sensitivity to DFMO. DIPG cells compensate for ODC1 inhibition by upregulation of the polyamine transporter SLC3A2. Treatment with the polyamine transporter inhibitor AMXT 1501 reduces uptake of polyamines in DIPG cells, and co-administration of AMXT 1501 and DFMO leads to potent in vitro activity, and significant extension of survival in three aggressive DIPG orthotopic animal models. Collectively, these results demonstrate the potential of dual targeting of polyamine synthesis and uptake as a therapeutic strategy for incurable DIPG., Diffuse intrinsic pontine glioma (DIPG) is an almost incurable malignant childhood brain tumor. Here, the authors show that the polyamine synthetic pathway is activated in DIPG and that the dual targeting of polyamine synthesis and uptake results in prolonged survival in animal models.
- Published
- 2021