Developing Novel Therapies for Neuroblastoma and Rhabdomyosarcoma

开发神经母细胞瘤和横纹肌肉瘤的新疗法

• 批准号: 9556370
• 负责人: Javed Khan
• 金额: $ 23.72万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9556370
• 关键词: Animal Model; Antigens; Apoptosis; Biological Assay; Cell Death; Cell Line; Child; Childhood; Clinical Trials; Down-Regulation; Drug Combinations; Drug Compounding; FDA approved; FOXO1A gene; Gene Targeting; Genes; Genome; Genomic Library; Growth; Human; Isotopically-Coded Affinity Tagging; Lead; Libraries; MYCN gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Methods; Mutate; Neuroblastoma; Normal tissue morphology; PAX3 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I/II Trial; Preclinical Drug Evaluation; Preclinical Testing; Proteins; Publishing; RNA Interference; RNA interference screen; Recommendation; Resources; Rhabdomyosarcoma; Screening for Neuroblastoma; System; Technology; Translating; Translational Research; Xenograft Model; Xenograft procedure; cancer therapy; differential expression; disorder risk; drug mechanism; fusion gene; gene repression; high risk; kinase inhibitor; novel therapeutics; programs; response; synergism

For neuroblastoma are using four cell lines, two MYCN not-amplified and two MYCN amplified cell line that can be grown in a xenograft model. For RMS we are using ten cell lines, tow with PAX3-FOXO1 fusion genes and two with RAS pathway mutated genes. Among other assays we will use the Incutyte system. For the siRNA screen we will use a druggable genome library of over 6000 genes developed by National Center for Advancing Translational Sciences (NCATS). For the drug screen we will use single agent and combination responses of a panel of 1916 drugs (Mechanism Interrogation Plate (MIPE-v4) Library) also developed by NCATS. The content of this library include 765 FDA approved compounds, 49 of which are approved for cancer therapy, 460 in clinical trials (phase 1, 2 or 3), 149 kinase inhibitors. For 1915 of these compounds, the target or mechanism of action is known. The most promising targets and the appropriate siRNA or drug combination will be further evaluated in the xenograft animal models as outlined above. All positive hits will be further screened in a wider panel of NB and RMS Xenografts which will be part of a panel of the Pediatric Preclinical Testing Program (PPTP) which is currently being utilized as a pipeline to screen new drugs and make recommendation for human pediatric phase 1/2 trials (http://ctep.cancer.gov/resources/child.html.)

对于神经母细胞瘤，使用四种细胞系，两种MYCN未扩增的细胞系和两种MYCN扩增的细胞系，其可以在异种移植模型中生长。对于RMS，我们使用10个细胞系，两个具有PAX 3-FOXO 1融合基因，两个具有RAS途径突变基因。在其他检测中，我们将使用Incutyte系统。对于siRNA筛选，我们将使用由国家推进转化科学中心（NCATS）开发的超过6000个基因的可药用基因组文库。对于药物筛选，我们将使用也由NCATS开发的一组1916种药物（机制询问板（MIPE-v4）库）的单一药物和组合反应。该库的内容包括765种FDA批准的化合物，其中49种被批准用于癌症治疗，460种在临床试验中（1，2或3期），149种激酶抑制剂。对于这些化合物中的1915种，作用的靶点或机制是已知的。最有希望的靶标和适当的siRNA或药物组合将在如上所述的异种移植动物模型中进一步评估。所有阳性结果将在更广泛的NB和RMS异种移植物组中进一步筛选，这些异种移植物组将成为儿科临床前试验计划（PPTP）组的一部分，该计划目前正被用作筛选新药的管道，并为人类儿科1/2期试验提供建议（http：//ctep.cancer.gov/resources/child.html）。