In 2018 Dr. David Ziegler and Dr. Maria Tsoli of Children's Cancer Institute proposed an innovative study demonstrating the anticancer potential of polyamine pathway inhibitors in preclinical models of DIPG. This project was approved for funding by the DIPG/DMG Collaborative and The Cure Starts Now and here are the results:
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.
Results
Dual inhibition of polyamine synthesis and transport enhances survival in orthotopic models of DIPG. ...This result was replicated in second patient-derived DIPG cells grown as an orthotopic animal model (HSJD-DIPG007) where two thirds of the mice survived until the endpoint.
Research Update
Through a separate grant funded provided by the DIPG/DMG Collaborative and The Cure Starts Now, this drug combination will soon be available as a Phase I/II clinical trial for patients! You can watch the grant check presentation below:
