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

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

doi:10.1038/s41467-021-20896-z

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.

Highlights

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%
Ornithine decarboxylase 1 (ODC1) protein and mRNA levels were increased in a panel of patient-derived H3K27M DIPG cell cultures compared with three normal human astrocyte cultures (NHA, P000302, RA038), while SAT1 mRNA levels were decreased (Fig. 1c–e, Supplementary Fig. 4)
To determine whether higher levels of polyamine synthetic enzymes were associated with increased polyamine levels in vivo, we measured the levels of putrescine, a polyamine synthesized directly from ODC1, in the brains of xenografted animals

Summary

Introduction

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%. 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. These results demonstrate the potential of dual targeting of polyamine synthesis and uptake as a therapeutic strategy for incurable DIPG. An adult clinical trial is currently underway for the combination of DFMO with AMXT 1501 (NCT03536728)

Methods

Results

Conclusion