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.

摘要 弥漫性桥脑胶质瘤(DIPG)是一种无法治愈的儿童癌症。确诊后的中位生存期不到2 五年的总体存活率只有1%。DIPG是不能手术的，尸检组织来源的细胞的异种移植模型 谱线是分子研究的中流砥柱。为了识别新的分子靶点，我们进行了第一个非靶向的 DIPG的代谢组学。我们利用已发表的DIPG基因表达数据和我们自己的基因进行网络整合 DIPG品系的表达数据，以可视化和解释DIPG代谢组的变化。我们的初步研究发现 DIPG中的一个新的分子靶点。我们强大的体外和体内数据表明，DIPG突变H3K27M 上调新的嘌呤代谢酶ATIC是治疗DIPG的新靶点。我们观察到 虽然CRISPR敲除ATIC基因极大地提高了DIPG肿瘤小鼠的存活率，但仅有抗叶酸ATIC抑制剂. 在降低DIPG增长方面不是很有效。通过进一步的代谢组学分析，我们确定了潜在的机制 DIPG中抗叶酸耐药性的研究以及克服抗叶酸耐药性的联合策略。在此应用程序中， 使用分子和遗传工具，抗叶酸和一碳代谢的抑制剂，我们将检查 ATIC抑制从头合成嘌呤、DIPG生长和扩散的生物学后果 两种独立的DIPG小鼠模型的动物存活率。