ATIC is a novel molecular target in diffuse intrinsic pontine glioma

摘要 弥漫性内在脑桥胶质瘤（DIPG）是一种无法治愈的儿童癌症。诊断后的中位生存期小于2 5年总生存率仅为1%。DIPG是不可手术的，尸检组织衍生细胞的异种移植模型 线是分子研究的支柱。为了确定新的分子靶点，我们进行了第一次非靶向的 DIPG的代谢组学。我们使用Network Integration与已发表的DIPG基因表达数据，以及我们自己的基因 DIPG系的表达数据，以可视化和解释DIPG代谢组的变化。我们的初步研究发现 DIPG中的新分子靶点。我们强有力的体外和体内数据表明，DIPG突变H3K27M 上调从头嘌呤代谢酶ATIC，其是DIPG中的新治疗靶点。我们观察到 虽然CRISPR敲除ATIC大大提高了DIPG肿瘤小鼠的存活率，但单独使用抗叶酸ATIC抑制剂， 在减少DIPG生长方面不是很有效。通过进一步的代谢组学分析，我们确定了潜在的机制， 抗叶酸药物耐药性的DIPG和克服抗叶酸药物耐药性的联合策略。在本申请中， 使用分子和遗传工具，抗叶酸剂和一碳代谢抑制剂，我们将研究的程度和 ATIC抑制对从头嘌呤生物合成、DIPG生长和播散以及总体的生物学后果 在两个独立的DIPG小鼠模型中的动物存活率。

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.