Molecular Targeting of Developmental Cancers in Children

儿童发育性癌症的分子靶向

• 批准号: 7431793
• 负责人: Richard John O'REILLY
• 金额: $ 251.11万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-21 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7431793
• 关键词: Molecular; Targeting; Developmental; Cancers; Children

DESCRIPTION (provided by applicant): This Program Project proposes an interactive multidisciplinary program of research into the genetics, molecular pharmacology, immunology and experimental therapy of the malignancies of the developing nerve, bone and muscle affecting children. The overall objective is: the identification, functional analysis and targeted therapeutic modification of genes and gene products uniquely or differentially expressed by the developmental malignancies of childhood. The Program Project has 4 research projects and 5 cores. Project I proposes to identify distinctive signatures of gene expression that define therapeutically relevant subclasses of these developmental tumors and to identify genes and pathways that provide potential targets for drug and immune-based therapy by virtue of their differential expression or altered function. Project II proposes to evaluate the function of the unique fusion genes that characterize Ewing's sarcoma, alveolar rhabdomyosarcoma and desmoplaslic small round cell tumor (DSRCT), to identify their targets and to characterize the alterations in gene expression and tumor cell function associated with their inhibition. Project IV proposes to evaluate novel ScFv streptavidin conjugate-based strategies for delivering radioconjugates, cytokines or effector cells to tumors to enhance tumor targeted activity and to reduce toxicities currently associated with non-specific uptake of native antibodies or antibody conjugates in organs such as the liver or the kidneys. Project V proposes to evaluate the anti-tumor activity of T lymphocytes generated from the blood of tumor bearing and normal hosts by sensitization with peptides derived from oncofetal proteins differentially expressed by developmental tumors of childhood. Practicable strategies will also be developed for generating T cells specific for peptides derived from these oncofetal proteins from patients not sharing common HLA alleles. The anti-tumor activity of T cells specific for novel epitopes will be compared with that of T cells generated against known immunogenic tumor peptides, as will be their capacity to home to and induce regressions of tumors in xenografted mice. Based on these studies, a phase I trial evaluating T cells specific for WT1 peptides in the treatment of WT1 malignancies of childhood will be conducted. The Program Project also includes 5 cores, a Pathology Core for evaluation of clinically annotated specimens, a Clinical Core to ensure appropriate accrual and careful evaluation of uniformly treated patients afflicted with these developmental tumors, a Preclinical Testing Core to assess and validate the activity of agents targeting genes or gene pathways found to be differentially expressed in specific developmental tumors against well-characterized tumor cell lines and, as appropriate, patient derived tumor cell populations both in vitro and in NOD/SClD xenograft models, a Biostatistics Core to guide the design of experiments in in vitro and in vivo models and to provide relational bioinformatic support for analyses of patterns of gene expression and an Administrative Core to enhance communication, prioritize efforts and provide appropriate scientific interchange and oversight.

描述（由申请人提供）： 该计划项目提出了一个互动的多学科研究计划，涉及遗传学，分子药理学，免疫学和影响儿童的发育中神经，骨骼和肌肉恶性肿瘤的实验治疗。总体目标是：儿童发育性恶性肿瘤独特或差异表达的基因和基因产物的鉴定、功能分析和靶向治疗修饰。 该计划项目有4个研究项目和5个核心。 项目I提出识别基因表达的独特特征，其定义这些发育性肿瘤的治疗相关亚类，并识别通过其差异表达或改变的功能为药物和基于免疫的治疗提供潜在靶点的基因和途径。 项目II建议评估尤因肉瘤，腺泡状横纹肌肉瘤和促结缔组织增生性小圆细胞瘤（DSRCT）的独特融合基因的功能，以确定其靶点，并表征与其抑制相关的基因表达和肿瘤细胞功能的改变。项目IV提出评估基于新型ScFv链霉亲和素缀合物的策略，用于将放射性缀合物、细胞因子或效应细胞递送至肿瘤，以增强肿瘤靶向活性并降低目前与器官（如肝脏或肾脏）中天然抗体或抗体缀合物的非特异性摄取相关的毒性。项目V建议评价T淋巴细胞的抗肿瘤活性，所述T淋巴细胞通过用源自儿童发育性肿瘤差异表达的癌胚蛋白的肽致敏而从荷瘤宿主和正常宿主的血液产生。还将开发用于产生T细胞的实用策略，所述T细胞对来自不共享共同HLA等位基因的患者的这些癌胚蛋白的肽具有特异性。将对新表位具有特异性的T细胞的抗肿瘤活性与针对已知免疫原性肿瘤肽产生的T细胞的抗肿瘤活性进行比较，因为它们在异种移植小鼠中归巢和诱导肿瘤消退的能力也是如此。基于这些研究，将进行一项I期试验，评估WT 1肽特异性T细胞治疗儿童WT 1恶性肿瘤的效果。该计划项目还包括5个核心，一个病理学核心，用于评估临床注释标本，一个临床核心，以确保适当的积累和仔细评估统一治疗的患者患有这些发育性肿瘤，临床前测试核心，用于评估和验证靶向在特定发育肿瘤中差异表达的基因或基因通路的药物对良好发育的肿瘤的活性。在体外和NOD/SClD异种移植模型中表征的肿瘤细胞系和适当的患者来源的肿瘤细胞群，指导体外和体内模型中实验设计的生物统计学核心，并为基因表达模式的分析提供相关的生物信息学支持，以及增强沟通的管理核心，确定各项努力的优先次序，并提供适当的科学交流和监督。