DDRE-09. THERAPEUTIC TARGETING OF PURINE METABOLISM IN DIPG

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 patient-derived DIPG cell lines by integrating an untargeted metabolomics analysis with RNA-sequencing data from the same lines which demonstrated dysregulated purine metabolism in these cells. Furthermore, we have identified putative driver mutations common to DIPG patients as the direct cause for this metabolic alteration. Purine metabolism provides the basic components of nucleotides needed for tumor proliferation and thus considered a high-priority target in cancer treatment. De novo purine biosynthesis (DNPS) is a sequential ten step enzymatic process resulting in the production of inosine monophosphate. The DNPS enzymes co-localize into a metabolon known as the purinosome and our preliminary data demonstrates DIPG cell lines are selectively sensitive to pharmacological and genetic disruption of purinosome formation. Interestingly, antifolate compounds that inhibit DNPS, but do not disrupt purinosome assembly, are cytotoxic to both DIPG cells and normal cell types. Strikingly, cell viability could be rescued by purine supplementation when inhibiting this pathway with antifolates, however inhibition of DNPS by disruption of purinosome assembly could not be rescued. Metabolomics analysis showed DIPGs have a preference for generating GMP over AMP which is exacerbated when purinosome assembly is disrupted. This is likely due to the duel-role of the DNPS enzyme ADSL which is required for AMP production.