EXTH-40. THERAPEUTICALLY TARGETING DE NOVO PURINE BIOSYNTHESIS IN DIFFUSE INTRINSIC PONTINE GLIOMA

Abstract

Abstract Diffuse intrinsic pontine glioma (DIPG) is an incurable brainstem malignancy in children with median survival less than 1 year and 5-year overall survival only 2 percent. Little progress has been made in treating this deadly disease due to its inoperable location and treatments aimed at targets defined in adult gliomas. Despite recent advances in genetic characterization of DIPGs there are still no targeted therapies that significantly improve overall survival. We recently generated a metabolic profile for DIPG elucidating an upregulation in purine metabolism, specifically in de novo purine biosynthesis (DNPB). Normally nucleotide salvage maintains cellular purine levels by recycling degraded bases, however DNPB is needed when purine levels are depleted. Purine metabolism provides the basic components of nucleotides needed for tumor proliferation and thus considered a high-priority target in cancer treatment. DNPB is a sequential ten step enzymatic process resulting in the production of inosine monophosphate. The last step in DNPB is carried out by the bifunctional enzyme ATIC which is upregulated in DIPG cell lines, and in patient tumors. Our preliminary data demonstrates DIPG cell lines are sensitive to pharmacological inhibition and genetic ablation of multiple enzymes in the DNPB pathway. Strikingly, cell viability could be rescued by purine supplementation when inhibiting this pathway except when ATIC is inhibited indicating the mechanism of cell death for ATIC inhibition is independent of purine nucleotide levels. Furthermore, there is a therapeutic window for targeting ATIC in DIPG cell lines relative to normal neural stem cells and normal human astrocytes. Metabolic flux experiments have demonstrated DNPB is upregulated in DIPG cell lines and the reason these cells are more sensitive to ATIC inhibition is likely related to the rapid accumulation of a cytotoxic metabolite upstream of ATIC. In vivo studies are currently underway in pre-clinical mouse models for DIPG.