NCI Pediatric In Vivo Testing Program - Leukemia

NCI 儿科体内检测计划 - 白血病

• 批准号: 10296642
• 负责人: Richard B Lock
• 金额: $ 45.5万
• 依托单位: UNIVERSITY OF NEW SOUTH WALES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10296642
• 关键词: Acute Lymphocytic Leukemia; Adopted; Adult; Advisory Committees; Animals; Aspirate substance; B-Cell Acute Lymphoblastic Leukemia; Biopsy; Bone Marrow; Cancer Patient; Cells; Characteristics; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Clinic; Clinical; Clinical Trials; Data; Diagnosis; Disease; Drug Combinations; Drug Kinetics; Drug Monitoring; Drug resistance; Engraftment; Ensure; Evaluation; Experimental Models; Exposure to; Failure; Foundations; Funding; Future; Gene Expression Profiling; Government; Health Benefit; Heterogeneity; Human; Immune; Industry Collaboration; Infant; Lesion; Leukemic Cell; Liver; Luciferases; MLL-rearranged leukemia; Malignant Childhood Neoplasm; Manuscripts; Measures; Methodology; Methods; Modeling; Molecular; Monitor; Mus; Mutation; New Agents; Organ; Outcome; Outcomes Research; PTPRC gene; Patients; Performance; Ph+ ALL; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Philadelphia Chromosome; Play; Preclinical Testing; Preparation; Publications; Quality Control; Quality of life; Relapse; Reproducibility; Research; Research Personnel; Resources; Role; SNP genotyping; Schedule; Spleen; Statutes and Laws; Structure; Systemic disease; T-Lymphocyte; Tail; Testing; Time; Toxic effect; Transplantation; United States National Institutes of Health; Variant; Veins; animal imaging; bioluminescence imaging; clinical development; cost estimate; design; drug response prediction; drug testing; early phase clinical trial; exome sequencing; experience; experimental study; flexibility; follow-up; high risk; improved; improved outcome; in vivo; in vivo evaluation; lentivirally transduced; leukemia; novel; novel therapeutics; patient derived xenograft model; peripheral blood; pre-clinical; programs; public-private partnership; response; standard of care; transcriptome sequencing; treatment response

Project Summary/Abstract This application seeks renewal of funding for a Research Program for acute lymphoblastic leukemia (ALL) in vivo testing as part of the NCI Pediatric In Vivo Testing Program (Ped-In Vivo-TP). Recent US Government legislation, combined with the relative rarity and higher cure rates of childhood cancer compared with adults, emphasize the importance of new agent preclinical testing programs aimed at maximizing the likelihood that only the most active drugs will be advanced into early phase clinical trials. The broad aim of this application is to improve the treatment options for children with aggressive and/or drug resistant ALL by prioritizing new drugs for clinical trials in the disease using state-of-the-art preclinical experimental models. This aim will be accomplished using a large panel of 90 pediatric ALL patient-derived xenografts (PDXs) that have undergone a high level of cell and molecular characterization and authentication. The PDXs to be used in this study were all established as models of orthotopic disease in immune- deficient (NOD/SCID or NSG) mice from direct patient explants without prior ex vivo culture. The PDXs develop as systemic disease in NSG mice and infiltrate the same major organs in mice as the primary disease in human patients. Engraftment and responses to treatment are monitored by measuring the proportion of human leukemia cells in the peripheral blood of mice on a weekly basis, which provides a reliable representation of overall leukemia burden in the animals. Where luciferase-expressing PDXs are available, this testing will be augmented by bioluminescence imaging of animals. The broad methodology will involve inoculation of PDX cells into NSG mice, a lag time to allow the disease to establish, followed by drug treatment and monitoring to assess drug responses. Methods of response evaluation have been developed using stringent criteria modeled after the clinical setting, in order to minimize the likelihood of over-predicting drug responses in mice leading to failure of drugs in the clinic. The proposed drug testing will adopt multiple formats, including conventional drug testing (6- 10 mice/group), single-mouse trial testing (1 PDX x 1 mouse x 1 drug) and testing of new agents in combination with standard-of-care drugs. In this fashion, this Research Program aims to test 8-10 new agents per year. By completing the major objectives outlined in this proposal, the long term health benefit aims to improve the treatment options and quality of life for children with aggressive forms of ALL who would otherwise succumb to their disease.

项目摘要/摘要 该应用程序寻求续签急性淋巴细胞白血病研究计划的资金 （所有）体内测试是NCI小儿体内测试程序（PED-IN VIVO-TP）的一部分。最近的美国 政府立法，加上相对稀有性和更高的儿童癌症治疗率 与成年人相比，强调了针对的新代理临床前测试计划的重要性 最大化只有最活跃的药物才能进入早期临床试验的可能性。 该应用的广泛目的是改善具有侵略性和/或的儿童的治疗选择 通过使用最先进的疾病中的临床试验新药优先考虑药物的全部抗药性 临床前实验模型。这个目标将使用90个小儿的大面板来实现 患者衍生的异种移植物（PDXS）经历了高水平的细胞和分子 表征和身份验证。 在本研究中使用的PDX均被确定为免疫中的原位疾病模型 来自直接患者外植体的缺乏（点头/SCID或NSG）小鼠，没有事先的离体培养。 PDXS 发展为NSG小鼠的全身性疾病，并在小鼠中浸入相同的主要器官与主要器官 人类患者的疾病。通过测量植入和对治疗的反应。 每周的小鼠外周血中人类白血病细胞的比例，这提供了 可靠的动物白血病负担的可靠表示。表达荧光素酶的PDX的其中 可用，该测试将通过动物的生物发光成像来增强。 广泛的方法将涉及将PDX细胞接种到NSG小鼠中，这是一个延迟的时间以允许 建立疾病，然后进行药物治疗和监测以评估药物反应。方法 响应评估是使用以临床环境建模的严格标准进行的，在 为了最大程度地减少过度预测的小鼠药物反应的可能性，导致药物失败 诊所。拟议的药物测试将采用多种格式，包括常规药物测试（6-- 10只小鼠/组），单小鼠试验测试（1 pdx x 1鼠标x 1药物）和新剂的测试 结合护理标准药物。以这种方式，该研究计划旨在测试8-10个新的新计划 每年的代理商。 通过完成本提案中概述的主要目标，长期健康福利旨在 改善所有人的侵略性形式的儿童的治疗选择和生活质量 否则屈服于他们的疾病。