Studies of Childhood Sarcomas

描述（由申请人提供）：本计划项目的最终目标是为晚期儿童肉瘤开发新的治疗方法。虽然超过70%的儿童肉瘤被认为是治愈的，但晚期或转移性疾病的结果仍然很差。具体来说，晚期或转移性尤文肉瘤、骨肉瘤或横纹肌肉瘤儿童的5年无事件生存率为30%或更低，而强化放化疗并没有显著改变这一结果。由于单独使用额外的细胞毒性药物不太可能提高治愈率，因此应探索替代和补充方法。该项目围绕三个独立但整合的信号通路，这些信号通路在儿童肉瘤中表现出活性。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NF-？B途径通过糖酵解途径调节肉瘤的代谢。我们的，和其他，数据表明，NF-？B信号影响STAT 3信号，NF-？B途径与mTOR相互作用以调节细胞代谢。项目2的重点是STAT 3信号如何调节肉瘤细胞的增殖和存活，以及开发LY 5，一种高度选择性的STAT 3变构抑制剂。我们表明，这两个NF-？B和IGF信号通路调节肉瘤细胞中的STAT 3。项目3将研究内在和获得性抵抗IGF靶向治疗方面的增殖，生存和血管生成。我们的数据表明，IGF-1保护对mTORC 1抑制诱导的细胞凋亡，并将探讨STAT 3和NF-？B对细胞凋亡的保护作用。该计划由三个共享资源支持。核心A（管理和生物统计）协调沟通，程序交互，并提供生物统计支持的集中机制。核心B（异种移植和细胞系）提供独特的儿童肉瘤小鼠模型和专业知识。Core C（Comparative Animal Core）提供组织病理学、新鲜犬肿瘤标本方面的专业知识，并为新型疗法的临床前测试提供自发性骨肉瘤犬。

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.