Studies of Childhood Sarcomas

儿童肉瘤的研究

基本信息

批准号：
8476016
负责人：
PETER J HOUGHTON
金额：
$ 150.53万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-05 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8476016
关键词：
Affect Animal Model Animals Antibodies Antineoplastic Agents Apoptosis B-insulin Biology Biometry Candidate Disease Gene Canis familiaris Cell Line Cell Proliferation Cells Child Childhood Clinical Combined Modality Therapy Communication Programs Cytotoxic agent Data Development Disease Disease-Free Survival Doctor of Philosophy Dose Glycolysis Goals In Vitro Insulin-Like Growth Factor I Insulin-Like Growth Factor II Maintenance Malignant Childhood Neoplasm Maximum Tolerated Dose Mediating Metabolic Metabolism Metastatic Ewing&apos s Sarcoma Modeling Molecular Mus NF-kappa B Outcome PTPRC gene Pathway interactions Patients Pharmaceutical Chemistry Population Preclinical Testing Principal Investigator Program Research Project Grants Radiation therapy Regulation Research Personnel Resistance Resource Sharing Rhabdomyosarcoma Role STAT3 gene Signal Pathway Signal Transduction Somatomedins Specimen Survival Rate Testing Therapeutic Toxic effect Treatment outcome Tumor-Derived Vascular Endothelial Cell Warburg Effect Xenograft procedure angiogenesis chemotherapy combinatorial comparative drug development genotoxicity human FRAP1 protein improved in vivo Model inhibitor/antagonist malignant phenotype mouse model neoplastic cell novel novel therapeutic intervention novel therapeutics osteosarcoma preclinical evaluation programs sarcoma therapeutic target tumor

项目摘要

DESCRIPTION (provided by applicant): The ultimate goal of this Program Project is to develop novel therapeutic approaches for advanced childhood sarcoma. While over 70% of children with sarcoma are considered cured, the outcome is still poor for those with advanced or metastatic disease. Specifically, the 5-year event free survival rates are 30 percent or less in children with advanced or metastatic Ewing sarcoma, osteosarcoma or rhabdomyosarcoma and intensive chemo-radiotherapy has not significantly altered this outcome. As additional cytotoxic drugs alone are unlikely to increase cure rates, alternative and complimentary approaches should be explored. This Program centers around three separate but integrated signaling pathways shown to be active in childhood sarcomas. The projects will characterize the interrelationship of these pathways and identify combinatorial inhibitory approaches most likely to yield biologic activity in the clinical setting. Project 1 will define the role of the classicalNF-?B pathway in regulating metabolism of sarcomas through a shift to the glycolytic pathway. Our, and other, data indicate that NF-?B signaling impacts STAT3 signaling and that components of the NF-?B pathways interact with mTOR to modulate cellular metabolism. Project 2 focuses on how STAT3 signaling regulates the proliferation and survival of sarcoma cells, and on the development LY5, a highly selective allosteric inhibitor of STAT3. We show that both NF-?B and IGF signaling pathways regulate STAT3 in sarcoma cells. Project 3 will examine intrinsic and acquired resistance to IGF-targeted therapies with respect to proliferation, survival and angiogenesis. Our data demonstrate that IGF-1 protects against apoptosis induced by mTORC1 inhibition and will explore the role of STAT3 and NF-?B in protection from apoptosis. The Program is supported by three shared resources. Core A (Administration and Biostatistics) coordinates communication, program interactions, and provides a centralized mechanism for biostatistical support. Core B (Xenograft and Cell Line) provides unique mouse models of childhood sarcoma and expertise. And Core C (Comparative Animal Core) supplies expertise in histopatholgy, fresh canine tumor specimens, and access to dogs with spontaneous osteosarcoma for preclinical testing of novel therapeutics.

描述（由申请人提供）：该计划项目的最终目标是为高级童年肉瘤开发新颖的治疗方法。尽管有超过70％的肉瘤儿童被认为是治愈的，但对于患有晚期或转移性疾病的患者来说，结果仍然很差。具体而言，患有晚期或转移性肉瘤，骨肉瘤或横纹肌肉瘤和强化化学疗法疗法的儿童的5年无事件生存率为30％或更少。由于仅另外的细胞毒性药物就不太可能提高治愈率，因此应探索替代方法和免费方法。该程序以三个单独但集成的信号通路为中心，显示出在儿童肉瘤中活跃的。这些项目将表征这些途径的相互关系，并确定最有可能在临床环境中产生生物学活性的组合抑制方法。项目1将定义经典途径在调节肉瘤的代谢中通过转移到糖酵解途径的作用。我们的和其他数据表明，NF-？B信号传导会影响STAT3信号传导，并且NF-？B途径的组成部分与MTOR相互作用以调节细胞代谢。项目2的重点是STAT3信号如何调节肉瘤细胞的增殖和存活，以及开发LY5，这是一种高度选择性的STAT3的变构抑制剂。我们表明，NF-？B和IGF信号通路都调节肉瘤细胞中的STAT3。项目3将检查有关增殖，生存和血管生成的内在耐药性和对IGF靶向疗法的抗性。我们的数据表明，IGF-1可以预防MTORC1抑制引起的凋亡，并将探索STAT3和NF-？B在保护凋亡中的作用。该计划由三个共享资源支持。核心A（管理和生物统计学）协调通信，程序相互作用，并为生物统计支持提供了集中的机制。 Core B（异种移植和细胞系）提供了儿童肉瘤和专业知识的独特小鼠模型。和核心C（比较动物核心）提供组织疗法，新鲜犬类肿瘤标本的专业知识，并提供具有自发性骨肉瘤的狗的途径，用于对新疗法的临床前测试。