Pediatric Preclinical Testing Consortium - Leukemia

儿科临床前测试联盟 - 白血病

基本信息

批准号：
9118109
负责人：
Richard B Lock
金额：
$ 38.57万
依托单位：
UNIVERSITY OF NEW SOUTH WALES
依托单位国家：
美国
项目类别：
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/9118109
关键词：
Acute Lymphocytic Leukemia Acute T Cell Leukemia Adult Animals B-Lymphocytes Biopsy Bone Marrow Bone Marrow Transplantation Cancer Patient Cells Characteristics Child Childhood Childhood Acute Lymphocytic Leukemia Clinical Clinical Trials Clofarabine DNA Interstrand Crosslinking Data Development Diagnosis Disease Drug Evaluation Drug resistance Engraftment Ensure Evaluation Exhibits Experimental Designs Experimental Models Exposure to Funding Future Health 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 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 cost design drug testing follow-up high risk improved in vivo lentivirally transduced leukemia novel novel therapeutics peripheral blood pre-clinical programs repaired research study response success treatment response

项目摘要

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（由申请人提供）：本申请为急性淋巴细胞白血病（ALL）体内测试研究项目寻求资金，作为儿科临床前测试联盟（PPTC）的一部分，因为与成人癌症相比，儿童癌症的发生率较低。每年只能进行有限数量的儿科临床试验，因此选择这些药物进行儿科临床试验至关重要。该申请的广泛目标是通过使用最先进的临床前实验优先考虑新药进行临床试验，改善患有侵袭性和/或耐药 ALL 的儿童的治疗选择。这一目标将通过使用在免疫缺陷小鼠中建立的大量细胞和分子定义的异种移植物来实现，在 5 年内每年测试 6-10 种新药物和/或其组合，并保持较高的技术质量，研究中使用的异种移植物按原位疾病按计划生长，这意味着白血病在小鼠体内与人类患者的相同器官中发生。研究中使用的所有异种移植物均已建立。来自直接患者外植体，并且之前没有在体外传代。将通过测量小鼠外周血中人类白血病细胞的比例来监测移植和对治疗的反应，这提供了总体白血病的可靠代表。广泛的方法将使用一次最多 8 个异种移植物接种到小鼠体内，一段时间让疾病发展，然后是一段治疗和监测期以评估药物反应。为了每年测试 6-10 种新药物/组合，我们还建议在资助期间测试 3 个新假设，这些假设基于我们对原发疾病和异种移植物的细胞和分子特征的详细了解。还有正如之前对新药物体内异种移植药物反应的评估一样，通过完成本提案中概述的主要目标，我们的长期目标是改善患有侵袭性 ALL 的儿童的治疗选择和生活质量，否则他们将死于这种疾病。他们的疾病。