Studies of Childhood Sarcomas

描述(由申请者提供)：该计划项目的最终目标是开发治疗晚期儿童肉瘤的新方法。虽然超过70%的肉瘤儿童被认为是治愈的，但对于那些患有晚期或转移性疾病的儿童来说，结果仍然很差。具体地说，在患有晚期或转移性尤文肉瘤、骨肉瘤或横纹肌肉瘤的儿童中，5年无事件生存率为30%或更低，而强化放化疗并未显著改变这一结果。由于额外的细胞毒药物本身不太可能提高治愈率，应该探索替代和补充的方法。该计划围绕三个独立但整合的信号通路展开，这些信号通路在儿童肉瘤中表现活跃。这些项目将描述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活性的组合抑制方法。项目1将定义经典的核因子-？B途径在通过转移到糖酵解途径来调节肉瘤代谢中的作用。我们的和其他的数据表明，核因子-？B信号影响STAT3信号，核因子-？B通路的组成部分与mTOR相互作用，调节细胞新陈代谢。项目2集中在STAT3信号如何调节肉瘤细胞的增殖和存活，以及STAT3的一种高选择性变构抑制剂LY5的发展。我们发现，在肉瘤细胞中，核因子？B和胰岛素样生长因子信号通路都调节STAT3。项目3将研究IGF靶向治疗在增殖、存活和血管生成方面的内在和获得性耐药性。我们的研究结果表明，IGF-1对抑制mTORC1诱导的细胞凋亡具有保护作用，并将探讨STAT3和核因子-β在保护细胞凋亡中的作用。该计划得到三个共享资源的支持。核心A(管理和生物统计)协调沟通、程序交互，并为生物统计支持提供集中机制。CORE B(异种移植和细胞系)提供了独特的儿童肉瘤小鼠模型和专业知识。而Core C(比较动物核心)提供组织病理学、新鲜的犬类肿瘤标本以及对患有自发性骨肉瘤的犬进行临床前新疗法测试的专业知识。

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.