DIPG-03. Therapeutic targeting of purine biosynthesis in DIPG

Abstract

Diffuse intrinsic pontine glioma (DIPG) is an incurable brainstem malignancy in children. Little progress has been made in treating this deadly disease due to its inoperable location and treatments aimed at targets defined in adult gliomas. Currently there are no targeted therapies that significantly improve overall survival in patients with this disease. To this end, we are developing a metabolic profile for this disease by integrating metabolomics and gene expression data from cell lines derived from DIPG patient tumors. Our long-term goal is to significantly improve the overall survival of children with DIPG by identifying novel therapeutic targets. Central to this goal is our investigation into dysregulated purine metabolism in these tumors. We’ve integrated gene expression and metabolomic datasets for DIPG cells and identified a potential therapeutic target in the de novo purine biosynthesis (DNPB) pathway. Genetic knockout experiments confirmed that DIPG cells require the last enzyme in the DNPB pathway, ATIC, for survival. Furthermore, we have identified a compound that disrupts ATIC homo-dimerization, which is required for ATIC catalytic activity. Our preliminary data demonstrates this compound may offer clinical benefits over traditional antifolates that target this same pathway; however, the mechanism leading to selective cytotoxicity was unclear. Antifolates such as methotrexate competitively inhibit folate binding sites in multiple enzymes within this pathway; however, there are known mechanisms of resistance to these drugs. We show that the ATIC dimerization inhibitor differs from the antifolates by disrupting a multi-enzyme complex known as the purinosome, which requires intact, functional ATIC for assembly. Furthermore, targeting ATIC through genetic and pharmacological inhibition in vivo has extended survival in our PDX mouse model of DIPG.