Pediatric Preclinical Testing Consortium - Leukemia

儿科临床前测试联盟 - 白血病

• 批准号: 10300044
• 负责人: Richard B Lock
• 金额: $ 19.23万
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300044
• 关键词: Acute Lymphocytic Leukemia; Adult; Animals; B-Cell Acute Lymphoblastic Leukemia; BCL2L1 gene; Biopsy; Bone Marrow; Bone Marrow Transplantation; Cancer Patient; Cells; Characteristics; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Clinical Trials; Clofarabine; DNA Interstrand Crosslinking; Data; Diagnosis; Disease; Drug Evaluation; Drug resistance; Engraftment; Ensure; Evaluation; Exhibits; Experimental Designs; Experimental Models; Exposure to; Funding; Future; Human; Immune; In Vitro; Infant; Knowledge; Laboratories; Leukemic Cell; Liver; Luciferases; MDM2 gene; MLL-rearranged leukemia; Malignant Childhood Neoplasm; Malignant Neoplasms; Manuscripts; Measures; Methodology; Modeling; Molecular; Monitor; Mus; New Agents; Organ; PTPRC gene; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Philadelphia Chromosome; Preclinical Testing; Preparation; Publications; Quality Control; Quality of life; Relapse; Reproducibility; Research; Schedule; Short Tandem Repeat; Signal Transduction; Single Nucleotide Polymorphism; Spleen; T-Lymphocyte; TP53 gene; Tail; Testing; Therapeutic; Time; Toxic effect; Up-Regulation; Veins; Xenograft procedure; base; bioluminescence imaging; clinical development; cost estimate; design; drug testing; experimental study; follow-up; high risk; improved; in vivo; in vivo evaluation; lentivirally transduced; leukemia; novel; novel therapeutics; patient derived xenograft model; peripheral blood; pre-clinical; programs; repaired; response; success; treatment response

Project Summary/Abstract This application seeks funding for a Research Program for acute lymphoblastic leukemia (ALL) in vivo testing as part of the Pediatric Preclinical Testing Consortium (PPTC). Due to the less frequent occurrence of childhood cancers compared with adult cancers only a limited number of pediatric clinical trials can be conducted each year. Therefore, it is essential to select those drugs for pediatric clinical trials that have the maximum likelihood of success. 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 by using a large panel of cell and molecularly defined xenografts that are established in immune-deficient mice to test 6-10 new drugs and/or their combinations annually over a 5 year period, maintaining high technical quality, on schedule, and within the estimated costs. The xenografts to be used in the study grow as orthotopic disease, meaning that the leukemia develops in the same organs in mice as in human patients. All of the xenografts to be used in the study were established from direct patient explants, and were not previously passaged in vitro. Engraftment and responses to treatment will be monitored by measuring the proportion of human leukemia cells in the peripheral blood of mice, which provides a reliable representation of overall leukemia burden in the animals. The broad methodology will use panels of up to 8 xenografts at a time that are inoculated into mice, a period of time to allow the disease to develop, followed by a treatment and monitoring period to assess drug responses. In addition to testing 6-10 new agents/combinations annually, we have also proposed to test 3 novel hypotheses during the course of the funding period. These hypotheses are based on our detailed knowledge of the cell and molecular characteristics of the primary disease and the xenografts, as well as previous evaluation of in vivo xenograft drug responses to new agents. By completing the major objectives outlined in this proposal, in the long term we aim to improve the treatment options and quality of life for children with aggressive forms of ALL who would otherwise succumb to their disease.

项目概要/摘要 本申请为急性淋巴细胞白血病（ALL）体内研究项目寻求资金 作为儿科临床前测试联盟 (PPTC) 的一部分进行测试。由于次数较少 与成人癌症相比，儿童癌症的发生率只有有限的儿童癌症 每年可进行临床试验。因此，选择适合儿科用药的药物非常重要。 成功可能性最大的临床试验。该应用程序的主要目标是 通过优先考虑改善患有侵袭性和/或耐药性 ALL 儿童的治疗选择 使用最先进的临床前实验模型对该疾病进行临床试验的新药。这 目标将通过使用一大组细胞和分子定义的异种移植物来实现，这些异种移植物是 在免疫缺陷小鼠中建立，每年测试 6-10 种新药和/或其组合，超过一年 5 年期间，保持高技术质量，按时完成，并在预计成本范围内。 研究中使用的异种移植物作为原位疾病生长，这意味着白血病 小鼠的器官与人类患者的器官相同。所有要使用的异种移植物 研究是从直接患者外植体建立的，并且之前没有在体外传代。 将通过测量人类的比例来监测植入和对治疗的反应 小鼠外周血中的白血病细胞，提供了整体的可靠代表 动物的白血病负担。广泛的方法将一次使用最多 8 个异种移植物的面板 接种到小鼠体内，让疾病发展一段时间，然后进行治疗 以及评估药物反应的监测期。 除了每年测试 6-10 种新药物/组合外，我们还建议测试 3 种 资助期间的新假设。这些假设是基于我们的 原发疾病和异种移植物的细胞和分子特征的详细知识， 以及先前对新药体内异种移植药物反应的评估。通过完成 该提案中概述的主要目标，从长远来看，我们的目标是改善治疗方案 患有攻击性 ALL 的儿童的生活质量，否则他们会屈服于他们的攻击 疾病。