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(由申请者提供)：这个项目提出了一个互动的多学科研究计划，研究影响儿童的发育中的神经、骨骼和肌肉的恶性肿瘤的遗传学、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不同表达的基因和基因产物进行鉴定、功能分析和有针对性的治疗修饰。该计划项目有4个研究项目和5个核心。项目I建议识别定义这些发育性肿瘤的治疗相关亚类的独特基因表达特征，并识别因其差异表达或功能改变而为基于药物和免疫的治疗提供潜在靶点的基因和途径。项目二建议评估尤文氏肉瘤、肺泡型横纹肌肉瘤和结缔组织增生性小圆细胞肿瘤(DSRCT)特有的融合基因的功能，以确定它们的靶点，并表征与它们的抑制相关的基因表达和肿瘤细胞功能的变化。项目四建议评估基于单链抗体亲和素结合物的新策略，将放射性结合物、细胞因子或效应细胞输送到肿瘤，以增强肿瘤靶向活性，并减少目前与在肝脏或肾脏等器官中非特异性摄取天然抗体或抗体结合物相关的毒性。项目V建议通过用儿童发育性肿瘤差异表达的癌胎儿蛋白的多肽致敏，评估从荷瘤患者和正常宿主的血液中产生的T淋巴细胞的抗肿瘤活性。还将开发切实可行的策略，以产生针对来自不具有共同等位基因的患者的癌胎儿蛋白的多肽的特异性T细胞。针对新表位的T细胞的抗肿瘤活性将与针对已知免疫原性肿瘤多肽产生的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宿和诱导肿瘤退化的能力。在这些研究的基础上，将进行一项评估WT1多肽特异性T细胞治疗儿童WT1恶性肿瘤的I期试验。该计划项目还包括5个核心，一个用于评估临床注释样本的病理学核心，一个用于确保对患有这些发育性肿瘤的接受统一治疗的患者进行适当收益和仔细评估的临床核心，一个临床前测试核心，用于评估和验证针对在特定发育性肿瘤中发现差异表达的基因或基因通路的药物的活性，该药物在体外和在NOD/SCLD异种移植模型中适当地针对患者来源的肿瘤细胞群，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，以及一个行政核心，以加强沟通，确定努力的优先顺序，并提供适当的科学交流和监督。