ATIC is a novel molecular target in diffuse intrinsic pontine glioma

ATIC是弥漫性内源性脑桥胶质瘤的新型分子靶点

• 批准号: 10712984
• 负责人: Biplab Dasgupta
• 金额: $ 48.42万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-09 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712984
• 关键词: Adopted; Adult; Adult Glioma; Anabolism; Animals; Apoptosis; Autopsy; Biological; Biology; Brain Stem; Carbon; Cell Line; Cells; Child; Clinic; Clustered Regularly Interspaced Short Palindromic Repeats; Compensation; Data; Diagnosis; Diet; Diffuse intrinsic pontine glioma; Dimerization; Disease; Dose; Drug Combinations; Drug resistance; Electroporation; Enzyme Inhibition; Enzymes; Essential Genes; Folic Acid; Folic Acid Antagonists; Folic Acid Deficiency; Gene Expression; Genes; Genetic; Genetically Engineered Mouse; Glioma; Goals; Growth; H3 K27M mutation; Histones; Human; Hydroxymethyltransferases; Hypoxanthines; Immunocompetent; In Vitro; Joints; Knock-out; Location; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Metabolic Pathway; Metabolism; Methotrexate; Molecular; Molecular Target; Mus; Mutation; Nitrogen; Pathway Analysis; Pathway interactions; Patients; Publishing; Purines; Radiation; Radiation therapy; Resistance; Ribonucleotides; Role; SLC19A1 gene; Serine; Specificity; System; Testing; Therapeutic; Therapy trial; Tissues; Up-Regulation; Visualization; Xenograft Model; analog; cellular transduction; chemotherapy; cytotoxicity; dietary; druggable target; folate-binding protein; glioma cell line; improved; in utero; in vivo; inhibitor; insight; metabolic profile; metabolome; metabolomics; meter; mouse model; nerve stem cell; new therapeutic target; novel; novel therapeutics; overexpression; patient derived xenograft model; purine metabolism; synergism; tool; transcriptome sequencing; tumor; tumor growth

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.

抽象的 弥漫性内在桥脑胶质瘤（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 年，5 年总生存率仅为 1%。 DIPG 不可操作，尸检组织来源细胞的异种移植模型 线是分子研究的支柱。为了识别新的分子靶点，我们进行了第一次非靶向 DIPG 的代谢组学。我们使用网络集成与已发布的 DIPG 基因表达数据以及我们自己的基因 DIPG 细胞系的表达数据，用于可视化和解释 DIPG 代谢组的变化。我们的初步研究发现 DIPG 中的一个新分子靶点。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，这是 DIPG 的新治疗靶点。我们观察到 虽然通过 CRISPR 敲除 ATIC 极大地提高了患有 DIPG 肿瘤的小鼠的存活率，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 DIPG 中抗叶酸药物耐药性的研究以及克服抗叶酸药物耐药性的联合策略。在这个应用程序中， 使用分子和遗传工具、抗叶酸剂和一种碳代谢抑制剂，我们将检查其程度和 ATIC 抑制对从头嘌呤生物合成、DIPG 生长和传播以及总体的生物学影响 两个独立的 DIPG 小鼠模型中的动物存活率。