Studies of Childhood Solid Tumors

儿童实体瘤的研究

• 批准号: 7122843
• 负责人: PETER J HOUGHTON
• 金额: $ 165.62万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-08-01 至 2007-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7122843
• 关键词: clinical research; neoplasm /cancer pharmacology; pediatric neoplasm /cancer; pharmacokinetics

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.

描述（由申请人提供）： 我们的长期目标是提高儿童恶性实体瘤的治愈率。重组后的计划更加关注发育治疗，在儿童癌症的独特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设，随后设计临床试验，模拟这些模型中发现的最佳时间表和全身暴露。这种方法已经通过我们的临床项目得到了验证，其中喜树碱，靶向DNA拓扑异构酶I的药物，在儿科患者的I/II期试验中表现出非常显著的活性。在本申请中，我们提出的研究，将导致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性药物与信号转导通路的抑制剂。 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性剂组合的治疗策略。项目24建立在这样一个发现的基础上，即在酵母中调节细胞周期检查点的基因的亚型等位基因赋予喜树碱显著的超敏性 和雷帕霉素。人类同源物将被克隆，它们的功能将被确定，它们在哺乳动物细胞中决定药物敏感性的作用将被确定。项目25将集中于已知的DNA损伤反应途径如何决定细胞命运喜树碱，以及缺氧诱导的应激如何影响p53指导的细胞命运。项目26将重点关注缺氧或营养应激如何通过未折叠蛋白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建立在显示ZD 1839（ErbB 1抑制剂）有效抑制ABC转运蛋白（BCRP/MRP 4）的结果的基础上，该转运蛋白赋予喜树碱药物耐药性。将探索ZD 1839在逆转耐药性和改变临床使用的喜树碱药理学方面的作用。项目10包括拓扑替康和伊立替康的I期和II期临床试验，每项试验均基于我们的实验室和临床前数据。这些方案得到了药代动力学和药物基因组学研究的支持，这些研究确保了最佳的全身暴露，生物学研究旨在增加我们对决定喜树碱拓扑异构酶I抑制剂单独或联合使用的治疗效果的参数的理解。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，以测试 mTOR靶向治疗是否对儿童实体恶性肿瘤有治疗意义。