Studies of Childhood Solid Tumors

描述(由申请人提供)： 我们的长期目标是提高儿童恶性实体肿瘤的治愈率。重组后的计划更加注重发展疗法，在独特的儿童癌症异种移植模型中测试从非哺乳动物和哺乳动物实验系统开发的实验室驱动的假说，随后设计的临床试验模拟时间表和全身暴露被发现在这些模型中是最佳的。这一方法已经通过我们的临床项目得到了验证，其中针对DNA拓扑异构酶I的喜树碱药物在儿科患者的I/II期试验中显示出非常显著的活性。在这项应用中，我们提出了一些研究，这些研究将有助于更好地了解拓扑异构酶抑制剂的敏感性或耐药性，并将开始整合细胞毒药和信号转导途径的抑制剂。项目23继续研究mTOR信号在肿瘤细胞生长和存活中的作用。研究将探索将mTOR抑制剂CCI-779(一种雷帕霉素酯)与IGF-I受体拮抗剂和细胞毒剂相结合的治疗策略。项目24的基础是发现酵母中调节细胞周期检查点的基因的亚型等位基因对喜树碱具有显著的超敏反应。 和雷帕霉素。人类同源物将被克隆，它们的功能被定义，它们在哺乳动物细胞中决定药物敏感性的作用被确定。项目25将侧重于了解DNA损伤反应通路如何决定细胞对喜树碱的命运，以及低氧诱导的应激如何影响P53导向的细胞命运。项目26将侧重于低氧或营养压力如何通过未折叠的蛋白质反应途径影响细胞对拓扑异构酶II靶向药物和DNA交联药物的敏感性。项目27建立在结果的基础上，结果表明ZD1839(一种ErbB1抑制剂)有效地抑制了对喜树碱药物产生耐药性的ABC转运蛋白(BCRP/MRP4)。将探讨ZD1839在逆转喜树碱耐药和改变临床使用喜树碱药理方面的作用。项目10包括拓扑替康和伊立替康的第一阶段和第二阶段临床试验，每一项试验都基于我们的实验室和临床前数据。这些方案得到了确保最佳全身暴露的药代动力学和药物基因组学研究的支持，以及旨在增加我们对决定基于喜树碱的拓扑异构酶I抑制剂单独或联合使用的疗效的参数的生物学研究的支持。我们还将评估雷帕霉素酯CCI-779，单独或与长春新碱联合使用进行测试 MTOR靶向治疗对儿童实体肿瘤是否具有治疗意义。

DESCRIPTION (provided by applicant): Our long-term goal is to advance cure rates for children with malignant solid tumors. The restructured program has an increased focus on developmental therapeutics, testing laboratory driven hypotheses developed from non-mammalian and mammalian experimental systems, in unique xenograft models of childhood cancers, with subsequent design of clinical trials that simulate schedules and systemic exposures found optimal in these models. This approach has been validated through our clinical project, where camptothecins, drugs that target DNA topoisomerase I, have demonstrated very significant activity in Phase I/II trials in pediatric patients. In this application we propose studies that will lead to a greater understanding of sensitivity or resistance to topoisomerase inhibitors, and will start of integrate cytotoxic agents with inhibitors of signal transduction pathways. Project 23 continues studies of mTOR signaling in growth, and survival of tumor cells. Studies will explore the therapeutic strategy of combining the mTOR inhibitor CCI-779, a rapamycin ester, in combination with IGF-I receptor antagonists and cytotoxic agents. Project 24 builds on the finding that hypomorphic alleles of genes that regulate cell cycle checkpoints in yeast confer dramatic hypersensitivity to camptothecin and rapamycin. Human homologues will be cloned, their function defined and their role in determining drug sensitivity in mammalian cells determined. Project 25 will focus on how know DNA damage response pathways determine cellular fate to camptothecins, and how hypoxia induced stress influences p53-directed cell fate. Project 26 will focus on how hypoxia or nutritional stress influences cellular sensitivity to topoisomerase II-targeted drugs and DNA cross-linking drugs through the unfolded protein response pathway. Project 27 builds on results showing that ZD1839 (an ErbB1 inhibitor) potently inhibits ABC transporters (BCRP/MRP4) that confer resistance to camptothecin drugs. The role of ZD1839 in reversing drug resistance, and altering the pharmacology of clinically used camptothecins will be explored. Project 10 comprises Phase I and II clinical trials with topotecan and irinotecan each of which is based on our laboratory and preclinical data. These protocols are supported by pharmacokinetic, and pharmacogenomic studies that ensure optimal systemic exposure, and biological studies designed to increase our understanding of parameters that determine therapeutic efficacy of camptothecin-based topoisomerase I inhibitors used alone or in combination. We will also evaluate the rapamycin ester, CCI-779, alone or in combination with vincristine, to test whether mTOR-targeted therapy will have therapeutic significance in children with solid malignancies.