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

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.


Statistics
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To verify the reproducibility of these findings: All in vitro experiments were conducted 2 or more times. In vivo efficacy was tested in three different DIPG tumor models. All attempts at replication were successful.
Animals were assigned to various experimental groups at random.
The nature of the intervention meant that blinding was not possible, however each endpoint was confirmed by an independent observer. STR profiling.
All cell lines tested negative for mycoplasma contamination.
No commonly misidentified lines were used.
Pathogen-free, 5-7 week old female Balb/C nude mice were purchased from Animal Resources Centre (Perth, Australia) and kept at an ambient temperature of 18-22°C with a humidity of 45-65% under a 12-hour light cycle (7:00 am -7:00pm).
The study did not involve wild animals.
The study did not involve samples collected form the field.
All experiments were performed under approval by the Animal Use and Care Committees of University of New South Wales.