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）：该项目提出了一项交互式多学科研究项目，涉及影响儿童的发育中的神经、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：对儿童发育性恶性肿瘤独特或差异表达的基因和基因产物进行鉴定、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 提议识别基因表达的独特特征，定义这些发育性肿瘤的治疗相关亚类，并识别基因和通路，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。 项目 II 提议评估表征尤文肉瘤、肺泡横纹肌肉瘤和结缔组织小圆细胞肿瘤 (DSRCT) 的独特融合基因的功能，以确定其靶标并表征与其抑制相关的基因表达和肿瘤细胞功能的变化。项目 IV 建议评估基于 ScFv 链霉亲和素缀合物的新型策略，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减少目前与肝脏等器官中天然抗体或抗体缀合物的非特异性摄取相关的毒性或肾脏。 Project V 提议通过用源自儿童发育性肿瘤差异表达的癌胎儿蛋白的肽致敏来评估从荷瘤宿主和正常宿主的血液中产生的 T 淋巴细胞的抗肿瘤活性。还将制定切实可行的策略，用于生成对来自不具有共同 HLA 等位基因的患者的这些癌胎儿蛋白衍生的肽具有特异性的 T 细胞。对新表位特异的 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 I 期试验，评估 WT1 肽特异性 T 细胞治疗儿童 WT1 恶性肿瘤的效果。该计划项目还包括 5 个核心，一个用于评估临床注释标本的病理学核心，一个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应计和仔细评估的临床核心，一个用于评估和验证药物活性的临床前测试核心在体外和 NOD/SClD 中针对已明确表征的肿瘤细胞系和（视情况而定）患者来源的肿瘤细胞群，发现在特定发育肿瘤中差异表达的靶向基因或基因通路异种移植模型，一个生物统计核心，用于指导体外和体内模型实验的设计，并为基因表达模式的分析提供相关的生物信息学支持，以及一个管理核心，以加强沟通，优先考虑工作并提供适当的科学交流和监督。