Pediatric Preclinical Testing Consortium - Leukemia

儿科临床前测试联盟 - 白血病

• 批准号: 9293262
• 负责人: Richard B Lock
• 金额: $ 39.02万
• 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 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9293262
• 关键词: Acute Lymphocytic Leukemia; Adult; Animals; B-Lymphocytes; 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; Liver; Luciferases; MDM2 gene; 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; design; drug testing; experimental study; follow-up; high risk; improved; in vivo; lentivirally transduced; leukemia; novel; novel therapeutics; peripheral blood; pre-clinical; programs; public health relevance; repaired; response; success; treatment response

 DESCRIPTION (provided by applicant): 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. Ths 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.

 描述（由应用程序提供）：本申请为小儿临床前测试联盟（PPTC）的一部分，为急性淋巴细胞白血病（ALL）的研究计划寻求资金。由于与成人癌症相比，儿童癌症的发生频率较小，因此每年只能进行有限数量的儿科临床试验。因此，必须选择这些药物进行小儿临床试验 具有成功的可能性。该应用的广泛目的是通过使用最先进的临床前实验模型对疾病中的临床试验进行优先考虑，以改善具有侵略性和/或耐药性的儿童的治疗选择。该目标将通过使用大量细胞和分子定义的异种移植物来实现，这些异种移植物在免疫缺陷小鼠中建立，以测试6-10种新药和/或它们的组合在5年内，在计划中保持高技术质量，按计划和估计的成本内保持高技术质量。该研究中使用的异种移植物随着原位疾病而生长，这意味着白血病在小鼠与人类患者的相同器官中发展。研究中使用的所有异种移植物均从直接患者外植体中建立，并且以前未在体外通过。植入和对治疗的反应将通过测量小鼠外周血中人类白血病细胞的比例来监测，这为动物的整体白血病燃烧提供了可靠的表示。广泛的方法将在接种小鼠中使用多达8个Xenographtics的面板，这是允许疾病发展的一段时间，然后进行治疗和监测期评估药物反应。除了每年测试6-10种新药物/组合外，我们还建议在资金期间测试3个新型假设。这些假设基于我们对原发性疾病和异种移植物细胞和分子特征的详细知识，以及先前对体内异种移植药物对新药物的反应的评估。通过完成该提案中概述的主要目标，从长远来看，我们旨在改善所有将屈服于其疾病的儿童的治疗选择和生活质量。