ATIC is a novel molecular target in diffuse intrinsic pontine glioma

Abstract Diffuse intrinsic pontine glioma (DIPG) is an incurable childhood cancer. Median survival after diagnosis is less than 2 years, and 5‐year overall survival is only 1%. DIPGs are inoperable, and xenograft models of autopsy tissue-derived cell lines are the mainstay for molecular studies. To identify novel molecular targets, we performed the first untargeted metabolomics of DIPG. We used Network Integration with published DIPG gene expression data, and our own gene expression data of DIPG lines to visualize and interpret changes in DIPG metabolome. Our preliminary studies uncovered a novel molecular target in DIPG. Our strong in vitro and in vivo data indicates that the DIPG mutation H3K27M upregulates the de novo purine metabolism enzyme ATIC which is a new therapeutic target in DIPG. We observed that while ATIC knockout by CRISPR greatly improved survival in mice with DIPG tumors, an antifolate ATIC inhibitor alone was not very effective in reducing DIPG growth. Through further metabolomics analysis we identified the potential mechanism of antifolate drug resistance in DIPG and combination strategies to overcome antifolate resistance. In this application, using molecular and genetic tools, antifolates and inhibitors of one carbon metabolism we will examine the extent and biological consequences of ATIC inhibition on de novo purine biosynthesis, DIPG growth and dissemination and overall animal survival in two independent mouse models of DIPG.