Molecular Targeting of Developmental Cancers in Children

儿童发育性癌症的分子靶向

• 批准号: 7096001
• 负责人: Richard John O'REILLY
• 金额: $ 248.73万
• 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/7096001
• 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项互动的多学科计划，对发展神经，骨骼和影响儿童的遗传学，分子药理学，免疫学和实验疗法的研究。总体目标是：通过儿童发育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，旨在确定基因表达的独特特征，这些特征定义了这些发育肿瘤的治疗相关亚类，并确定基因和途径，这些基因和途径通过其差异表达或功能改变，为药物和基于免疫的治疗提供潜在的靶标。 项目II提出的是评估特征的独特融合基因的功能，这些融合基因表征了Ewing的肉瘤，肺泡横纹肌肉瘤和去骨质体小圆形细胞肿瘤（DSRCT），以识别其靶标，并表征其基因表达和与抑制作用相关的基因表达和肿瘤细胞功能的变化。 IV项目提议评估新型SCFV链霉亲和素结合物的策略，以将放射性偶联物，细胞因子或效应细胞传递到肿瘤中，以增强肿瘤的靶向活性，并降低目前与当前非特异性摄取天然抗体或抗体抗体或抗体相结合的毒性。 Project V提出了通过用妇女发育肿瘤差异地表达的肽敏化来评估由肿瘤轴承和正常宿主血液产生的T淋巴细胞和正常宿主产生的T淋巴细胞的抗肿瘤活性。还将开发出可行的策略，以产生从不共享HLA等位基因的患者中衍生自这些源自蛋白质的肽的T细胞。将针对新表位的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细胞的抗肿瘤活性将进行比较，它们的能力将是其回家的能力并诱导异种移植小鼠中肿瘤的回归。基于这些研究，将进行一项评估WT1肽特异性T细胞在WT1儿童期治疗中的T细胞。该计划项目还包括5个核心，这是评估临床注释标本的病理核心，这是确保对患有这些发育性肿瘤的均匀治疗的患者进行适当的应计和仔细评估的临床核心，一种临床前测试核心，一种评估和验证针对特定的发育范围差异性的临界途径的药物的活性，以差异性地表达临床的活性，该病例是针对特定的细胞差异，这些途径是在特定的细胞中表达的，并且是在较大的细胞中表达的，这些细胞是在变形较大的情况下，并且是在变形较低的情况下，并且是隔离的细胞，这些细胞是在变形较大的细胞中，并且是在变形的情况下，并且是在变形的情况下，是较大的变形。体外和点数/SCLD异种移植模型的种群，这是一种指导体外和体内模型实验设计的生物统计学核心，并为基因表达模式的分析和行政核心提供相关的生物信息支持，以增强沟通，优先努力并提供适当的科学分解和监督。