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

Aaminah Khan, Laura D. Gamble, Dannielle H. Upton, Caitlin Ung, Denise M. T. Yu, Anahid Ehteda, Ruby Pandher, Chelsea Mayoh, Steven Hébert, Nada Jabado, Claudia L. Kleinman, Mark R. Burns, Murray D. Norris, Michelle Haber, Maria Tsoli and David S. Ziegler ()
Additional contact information
Aaminah Khan: Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney
Laura D. Gamble: Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney
Dannielle H. Upton: Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney
Caitlin Ung: Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney
Denise M. T. Yu: Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney
Anahid Ehteda: Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney
Ruby Pandher: Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney
Chelsea Mayoh: Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney
Steven Hébert: McGill University
Nada Jabado: McGill University Health Center
Claudia L. Kleinman: McGill University
Mark R. Burns: Aminex Therapeutics Inc.
Murray D. Norris: Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney
Michelle Haber: Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney
Maria Tsoli: Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney
David S. Ziegler: Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-20896-z

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