NCI Pediatric In Vivo Testing Program - Leukemia

NCI 儿科体内检测计划 - 白血病

基本信息

批准号：
10682420
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
项目类别：
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/10682420
关键词：
Acceleration Acute Lymphocytic Leukemia Acute T Cell Leukemia Adopted Adult Advisory Committees Animals B-Cell Acute Lymphoblastic Leukemia Biopsy Bone Marrow Bone Marrow Aspiration 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 Infiltration Lesion Leukemia, Lymphocytic, Acute, L2 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 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 data submission 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 skills standard of care transcriptome sequencing treatment response

项目摘要

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.

项目概要/摘要本申请寻求续订急性淋巴细胞白血病研究计划的资金 (ALL) 体内测试，作为 NCI 儿科体内测试计划 (Ped-In Vivo-TP) 的一部分。最近的美国政府立法，加上儿童癌症相对罕见且治愈率较高与成人相比，强调新药临床前测试计划的重要性最大限度地提高只有最活跃的药物进入早期临床试验的可能性。该应用程序的广泛目标是改善患有攻击性和/或通过优先使用最先进的技术对新药进行临床试验来治疗耐药性 ALL 临床前实验模型。这一目标将通过由 90 名儿童 ALL 组成的大型小组来实现患者来源的异种移植物（PDX）经过高水平的细胞和分子表征和认证。本研究中使用的 PDX 均被建立为免疫原位疾病模型。来自直接患者外植体的缺陷（NOD/SCID 或 NSG）小鼠，未经事先离体培养。 PDX 在 NSG 小鼠中发展为全身性疾病，并浸润与原发性小鼠相同的主要器官人类患者的疾病。通过测量每周检测小鼠外周血中人类白血病细胞的比例，这提供了动物总体白血病负担的可靠代表。表达荧光素酶的 PDX 如果可用，该测试将通过动物生物发光成像得到增强。广泛的方法将涉及将 PDX 细胞接种到 NSG 小鼠中，一段滞后时间以允许确定疾病，然后进行药物治疗和监测以评估药物反应。方法反应评估已根据临床环境制定了严格的标准，为了尽量减少过度预测小鼠药物反应导致药物失败的可能性诊所。拟议的药物测试将采用多种形式，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小鼠 x 1药物）和新药测试与标准治疗药物组合。以这种方式，该研究计划旨在测试 8-10 个新的代理每年。通过完成本提案中概述的主要目标，长期健康效益旨在改善患有侵袭性 ALL 的儿童的治疗选择和生活质量否则就会死于疾病。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effective targeting of NAMPT in patient-derived xenograft models of high-risk pediatric acute lymphoblastic leukemia.

DOI：
10.1038/s41375-019-0683-6
发表时间：
2020-06
期刊：
LEUKEMIA
影响因子：
11.4
作者：
Somers, Klaartje;Evans, Kathryn;Cheung, Leanna;Karsa, Mawar;Pritchard, Tara;Kosciolek, Angelika;Bongers, Angelika;El-Ayoubi, Ali;Forgham, Helen;Middlemiss, Shiloh;Mayoh, Chelsea;Jones, Luke;Gupta, Mahima;Kees, Ursula R.;Chernova, Olga;Korotchkina, Lioubov;Gudkov, Andrei, V;Erickson, Stephen W.;Teicher, Beverly;Smith, Malcolm A.;Norris, Murray D.;Haber, Michelle;Lock, Richard B.;Henderson, Michelle J.
通讯作者：
Henderson, Michelle J.

In vivo activity of the dual SYK/FLT3 inhibitor TAK-659 against pediatric acute lymphoblastic leukemia xenografts.

SYK/FLT3 双重抑制剂 TAK-659 对儿童急性淋巴细胞白血病异种移植物的体内活性。

DOI：
10.1002/pbc.30503
发表时间：
2023
期刊：
Pediatric blood & cancer
影响因子：
3.2
作者：
Hughes,Keira;Evans,Kathryn;Earley,EricJ;Smith,ChristopherM;Erickson,StephenW;Stearns,Tim;Philip,VivekM;Neuhauser,StevenB;Chuang,JeffreyH;Jocoy,EmilyL;Bult,CarolJ;Teicher,BeverlyA;Smith,MalcolmA;Lock,RichardB
通讯作者：
Lock,RichardB

Initial testing (stage 1) of the curaxin CBL0137 by the pediatric preclinical testing program.

DOI：
10.1002/pbc.26263
发表时间：
2017-04
期刊：
Pediatric blood & cancer
影响因子：
3.2
作者：
Lock R;Carol H;Maris JM;Kolb EA;Gorlick R;Reynolds CP;Kang MH;Keir ST;Wu J;Purmal A;Gudkov A;Kurmashev D;Kurmasheva RT;Houghton PJ;Smith MA
通讯作者：
Smith MA

Initial testing of VS-4718, a novel inhibitor of focal adhesion kinase (FAK), against pediatric tumor models by the Pediatric Preclinical Testing Program.

DOI：
10.1002/pbc.26304
发表时间：
2017-04
期刊：
Pediatric blood & cancer
影响因子：
3.2
作者：
Kurmasheva RT;Gorlick R;Kolb EA;Keir ST;Maris JM;Lock RB;Carol H;Kang M;Reynolds CP;Wu J;Houghton PJ;Smith MA
通讯作者：
Smith MA

Bioluminescence Imaging Enhances Analysis of Drug Responses in a Patient-Derived Xenograft Model of Pediatric ALL.

DOI：
10.1158/1078-0432.ccr-16-2392
发表时间：
2017-07-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Jones L;Richmond J;Evans K;Carol H;Jing D;Kurmasheva RT;Billups CA;Houghton PJ;Smith MA;Lock RB
通讯作者：
Lock RB