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

Author

Listed:
  • 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
    Centre for Childhood Cancer Research, UNSW Sydney)

  • Michelle Haber

    (Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney
    Centre for Childhood Cancer Research, 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
    Kids Cancer Centre, Sydney Children’s Hospital, High St)

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.

Suggested Citation

  • 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 &, 2021. "Dual targeting of polyamine synthesis and uptake in diffuse intrinsic pontine gliomas," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-20896-z
    DOI: 10.1038/s41467-021-20896-z
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    Cited by:

    1. Guoshu Bi & Jiaqi Liang & Yunyi Bian & Guangyao Shan & Yiwei Huang & Tao Lu & Huan Zhang & Xing Jin & Zhencong Chen & Mengnan Zhao & Hong Fan & Qun Wang & Boyi Gan & Cheng Zhan, 2024. "Polyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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