Molecular Targeting of Developmental Cancers in Children

项目描述（由申请人提供）：本项目提出了一个互动的多学科项目，研究影响儿童发育中的神经、骨骼和肌肉恶性肿瘤的遗传学、分子药理学、免疫学和实验治疗。总体目标是：鉴定，功能分析和靶向治疗修饰的基因和基因产物独特或差异表达的儿童发育恶性肿瘤。本项目有4个研究项目，5个核心。项目一提出确定确定这些发育性肿瘤治疗相关亚类的基因表达的独特特征，并确定通过其差异表达或改变功能为药物和免疫治疗提供潜在靶点的基因和途径。项目II拟评估Ewing肉瘤、肺泡横纹肌肉瘤和韧带增塑性小圆细胞瘤（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建议评估新的基于ScFv链亲和素偶联物的策略，用于将放射性偶联物、细胞因子或效应细胞递送到肿瘤中，以增强肿瘤靶向活性，并减少目前与肝脏或肾脏等器官中天然抗体或抗体偶联物的非特异性摄取相关的毒性。项目V拟通过儿童期发育性肿瘤差异表达的癌胎蛋白衍生肽致敏，评估荷瘤和正常宿主血液中产生的T淋巴细胞的抗肿瘤活性。还将开发可行的策略，以产生T细胞特异性肽，这些肽来源于不具有共同HLA等位基因的患者的癌胎蛋白。新表位特异性T细胞的抗肿瘤活性将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，以及它们在异种移植小鼠中归巢和诱导肿瘤消退的能力。基于这些研究，将进行一项评估WT1肽特异性T细胞治疗儿童WT1恶性肿瘤的I期试验。该项目还包括5个核心，一个是病理学核心，用于评估临床注释标本，一个是临床核心，用于确保对患有这些发育性肿瘤的统一治疗患者进行适当的累积和仔细评估，一个是临床前测试核心，用于评估和验证针对特定发育性肿瘤中发现的差异表达的基因或基因途径的活性，以对抗特征明确的肿瘤细胞系。一个生物统计学核心，用于指导体外和体内模型的实验设计，并为基因表达模式的分析提供相关的生物信息学支持；一个管理核心，用于加强沟通，优先考虑工作，并提供适当的科学交流和监督。

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.