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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：
8548303
负责人：
Yves A DeClerck
金额：
$ 45.64万
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/8548303
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 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 screening therapeutic development tumor tumor microenvironment

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.

该中心将被指定为EMDR中心，其使命是对EMDR机制进行基本调查，以确定EMDR途径的抑制剂，促进在急性淋巴细胞白血病和神经母细胞瘤儿童的临床试验中对其进行测试，并与科学界分享所获得的知识和开发的技术。通过广泛的合作，EMDR中心的7名研究人员将测试基本假设，即骨髓为ALL和神经母细胞瘤细胞提供了独特的微环境，使它们能够在药物诱导的损伤中存活，并促进耐药细胞的建立，这些耐药细胞是疾病复发和治疗失败的原因。因此，第二个假设是，用抑制剂阻断负责EMDR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测试，这些研究项目将检查儿童ALL和神经母细胞瘤中EMDR的3个特定的主要途径。所有项目将结合肿瘤细胞系和骨髓源性基质细胞的共培养和小鼠模型中的联合收割机实验。然后，项目将验证他们在ALL和神经母细胞瘤患者骨髓样本中的观察结果，这些样本将通过EMDR中心提供。所产生的数据将用于促进I/II期临床试验的实施，这些临床试验将由总部位于CHLA的2个儿科临床试验联盟进行。项目将探索新的概念，如糖基化，甲基化和肿瘤微环境燃料对EMDR发展的影响，产生新的小鼠模型和数据集，并开发药物筛选的新技术，通过NCI-TMEN与科学界分享。此外，EMDR中心将受益于与CHLA，USC和COH的几个学术实体的密切互动，同时将大大有助于扩大他们对肿瘤微环境的研究重点。