Center for Environment-Mediated Drug Resistance in Pediatric Cancer

环境介导的小儿癌症耐药性中心

基本信息

批准号：
8213000
负责人：
Yves A DeClerck
金额：
$ 50.31万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-20 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8213000
关键词：
Acute Lymphocytic Leukemia Age Biological Assay Bone Marrow CXCR4 gene Cancer Patient Cause of Death Cell Death Cell Line Cells Child Childhood Childhood Acute Lymphocytic Leukemia Childhood Leukemia Childhood Lymphoma Children&apos s Oncology Group Cities Clinical Trials Coculture Techniques Collaborations Communities Cultured Tumor Cells Data Data Set Development Disease Drug resistance Drug resistance pathway Ensure Environment Genetic Genetic Determinism Growth Factor Human Injury Interleukin-6 Intervention Investigation JAK2 gene Knowledge Knowledge Discovery Los Angeles Malignant Childhood Neoplasm Malignant Neoplasms Mediating Methylation Mission Modeling Mus Neoplasm Metastasis Neuroblastoma Only Child Pathway interactions Patients Pediatric Hospitals Pharmaceutical Preparations Phase Preclinical Drug Evaluation Primary Neoplasm Reagent Recurrence Relapse Research Research Personnel Research Project Grants Resistance Role STAT3 gene Sampling Screening procedure Signal Transduction Site Stem cells Stromal Cells Technology Testing Therapeutic Time Transgenic Mice Translating Treatment Failure Tumor Cell Line Xenograft procedure bone chemokine cytokine drug sensitivity glycosylation high risk improved inhibitor/antagonist innovation interest member mouse model neoplastic cell neuroblastoma cell new technology novel strategies pre-clinical prevent research study therapeutic development tumor

项目摘要

The mission of the Center, to be designated the EMDR Center, is to conduct fundamental inquiries on mechanisms responsible for EMDR in order to identify inhibitors of EMDR pathways, to promote their testing in clinical trials in children with ALL and neuroblastoma, and to share the knowledge acquired and the technology developed with the scientific community. Through extensive collaboration, the 7 investigators of the EMDR Center will test the fundamental hypothesis that the bone marrow provides a unique microenvironment for ALL and neuroblastoma cells which allows them to survive the injuries induced by drugs and promotes the establishment of drug-resistant cells that are responsible for disease recurrence and treatment failure. Accordingly, the secondary hypothesis is that blocking specific pathways responsible for EMDR with inhibitors will prevent the emergence of these drug-resistant cells. These hypotheses will be tested through 3 interrelated research projects that will examine 3 specific leading pathways of EMDR in childhood ALL and neuroblastoma. All projects will combine experiments in co-cultures of tumor cell lines and bone marrowderived stromal cells and in murine models. Projects will then validate their observations in bone marrow samples from patients with ALL and neuroblastoma, to be made available through the EMDR Center. The data generated will be used to promote the implementation of phase l/ll clinical trials, to be conducted by 2 pediatric clinical trials consortia headquartered at CHLA. Projects will explore new concepts such as the effects of glycosylation, methylation and tumor microenvironmental fuels on the development of EMDR, generate new mouse models and data sets, and develop new technology in drug screening that will be shared with the scientific community through the NCI-TMEN. Furthermore, the EMDR Center will benefit from closely interacting with several academic entities at CHLA, USC and COH, and at the same time will substantially contribute to expanding their research focus on the tumor microenvironment.

该中心的任务被指定为EMDR中心，是为了鉴定EMDR途径的抑制剂，在具有全部和神经母细胞瘤的儿童的临床试验中促进其测试，并与科学界共享知识以及与科学界开发的技术。通过广泛的合作，EMDR中心的7个研究者将检验以下基本假设：骨髓为所有人和神经细胞瘤细胞提供了独特的微环境，使它们能够在药物引起的伤害中生存并促进药物抗药性细胞的建立，从而负责疾病复发和治疗失败。因此，次要假设是阻止负责EMDR抑制剂的特定途径将防止这些耐药细胞的出现。这些假设将通过3个相互关联的研究项目进行检验，该项目将检查儿童时期和神经母细胞瘤的3个特定领先途径。所有项目都将在肿瘤细胞系和骨髓的基质细胞和鼠模型中的共同培养中结合实验。然后，项目将通过EMDR中心从患有所有和神经母细胞瘤患者的骨髓样品中验证其观察结果。生成的数据将用于促进L/LL临床试验的实施，该试验由总部位于CHLA的2个儿科临床试验财团进行。项目将探讨新概念，例如糖基化，甲基化和肿瘤微环境燃料对EMDR开发的影响，生成新的小鼠模型和数据集，并在药物筛查中开发新技术，这些技术将通过NCI-TMEN与科学界共享。此外，EMDR中心将受益于与CHLA，USC和COH的多个学术实体的紧密互动，同时将大大促进他们对肿瘤微环境的研究的关注。