PRECLINICAL DRUG AND BIOLOGIC TESTING

临床前药物和生物测试

• 批准号: 8506990
• 负责人: Nino Keshelava
• 金额: $ 21.02万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 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/8506990
• 关键词: Biological Assay; Biology; Cell Communication; Cell Line; Cells; Clinical Data; Clinical Investigator; Clinical Trials; Coculture Techniques; Collaborations; Combined Modality Therapy; Cultured Tumor Cells; Data Analyses; Disease; Drug Combinations; Generations; Human; IGF1R gene; Immunocompromised Host; In Vitro; Interleukin-6; Maximum Tolerated Dose; Mesenchymal; Modeling; Multi-Drug Resistance; Mus; Natural Killer Cells; Neuroblastoma; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase I Clinical Trials; Pre-Clinical Model; Research Personnel; STAT3 gene; Schedule; Testing; Tissues; Work; Xenograft Model; aurora-A kinase; cell bank; chemotherapeutic agent; combinatorial; cytotoxicity; design; high risk; in vivo; inhibitor/antagonist; instrument; lenalidomide; monocyte; neoplastic cell; neuroblastoma cell; novel therapeutics; pre-clinical; research clinical testing; research study; subcutaneous; tumor; tumor growth; tumor xenograft

The objective of the NANT Pre-Clinical Testing Lab is to facilitate the generation of hypothesis driven clinical trials within the NANT, and to provide guidance to NANT clinical investigators in prioritizing potential new therapeutics for phase I trials, and rational use of combinatorial therapy. The following Specific Aims will aid in achieving our objective: 1) Maintain a master cell bank of well-characterized human neuroblastoma cell lines. 2) Maintain DIMSCAN instrument in working order for use for experiments dealing with chemotherapeutic agents and IL-6, soluble IL-6, anti-IL-6 mAb CNTO 328, the STAT3 inhibitor stattic (Project 1), NK cells, anti-IGF1R mAb (Project 2), PI3K inhibitors, Aurora Kinase A type I and II inhibitors (Project 3), and drugs and drug combinations suggested by NANT investigators (Project 4). 3) Develop a "microenvironment" model by co-culturing tumor cells with representative microenvironment cells (e.g., monocytes, mesenchymal cells) to test by DIMSCAN therapies targeting tumor cell - microenvironment cell interaction (e.g., anti-IL-6 mAb; lenalidomide) (collaboration with Projects 1 and 2). 4) Conduct in vitro cytotoxicity assays using DIMSCAN and provide assistance to project investigators in designing experiments, instructing in use of DIMSCAN and analyzing of data. 5) Assess anti-tumor activity of selected combinations using subcutaneous and disseminated disease xenograft models of multi-drug-resistant human neuroblastomas in immunocompromised mice by 1) determining maximal tolerated dose (MTD) of selected drug combinations; 2) assessing pharmacodynamic evidence of drug activity at the MTD in tumor xenograft tissue; 3) assessing the effect of the most active combinations on tumor growth delay and mouse survival.

NANT 临床前测试实验室的目标是促进 NANT 内假设驱动的临床试验的生成，并为 NANT 临床研究人员提供指导，以优先考虑 I 期试验的潜在新疗法以及合理使用组合疗法。 以下具体目标将有助于实现我们的目标： 1) 维护具有良好特征的人类神经母细胞瘤细胞系的主细胞库。 2) 维持 DIMSCAN 仪器正常工作，用于处理化疗药物和 IL-6、可溶性 IL-6、抗 IL-6 mAb CNTO 328、STAT3 抑制剂 stattic（项目 1）、NK 细胞、抗 IGF1R mAb（项目 2）、PI3K 抑制剂、Aurora 激酶 A I 型和 II 型抑制剂（项目 3）以及药物的实验 以及 NANT 研究人员建议的药物组合（项目 4）。 3) 通过将肿瘤细胞与代表性微环境细胞（例如单核细胞、间充质细胞）共培养来开发“微环境”模型，以通过针对肿瘤细胞-微环境细胞相互作用的 DIMSCAN 疗法进行测试（例如抗 IL-6 mAb；来那度胺）（与项目 1 和 2 合作）。 4) 使用DIMSCAN进行体外细胞毒性测定，并为项目研究者设计实验、指导DIMSCAN的使用和数据分析提供帮助。 5) 通过 1) 确定所选药物组合的最大耐受剂量 (MTD)，使用免疫受损小鼠中多重耐药人神经母细胞瘤的皮下和播散性疾病异种移植模型来评估所选组合的抗肿瘤活性； 2) 评估肿瘤异种移植组织中 MTD 药物活性的药效学证据； 3) 评估最活跃的组合对肿瘤生长延迟和小鼠存活的影响。