Studies of Childhood Solid Tumors

儿童实体瘤的研究

• 批准号: 7498001
• 负责人: PETER J HOUGHTON
• 金额: $ 221.95万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7498001
• 关键词: Studies; Childhood; Solid; Tumors

DESCRIPTION (provided by applicant): The theme of our program continues to be the integration of basic laboratory studies, animal model evaluation, and clinical trials to develop improved treatment for childhood solid tumors. The program is tightly focused on new and innovative approaches to improving cytotoxic therapy, and integrating signaling inhibitors with cytotoxic therapies. The theme of the program, developmental therapeutics for solid tumors, incorporates basic studies of how cellular stress (growth factor signaling hypoxia, DNA damage) impacts on drug sensitivity in solid tumors. Emphasis has been placed on the identification of pathways upstream and downstream of DNA damage that may be targets for new therapy, and on growth factor receptors that are involved in angiogenesis and in survival of cells treated with cytotoxic agents. We have structured the program to encompass objectives that can be accomplished within this cycle of support, and objectives that, realistically, could take longer to fulfill, but that may represent radically new approaches to curative therapy. Project 1 continues therapeutic studies of IGF-IR/Akt/mTOR inhibitors, and the role of IGF-IR signaling in childhood cancers. Project 2 extends studies that have demonstrated mTOR signaling regulates cellular response to DNA damage, and mutation frequency. Project 3 continues studies that demonstrate activation of the unfolded protein response (UPR) modulates cell sensitivity to cytotoxic agents, and will examine UPR activation in clinical tumors. Project 4 will elucidate how antiangiogenic agents may modulate the pharmacology of cytotoxic agents (ABC transporters) and provide new insights into clinically relevant ways to evaluate and monitor specific changes in tumor vascularity based on noninvasive assessments of changes in tumor blood flow/vasculature (through MRI and ultrasonography). These studies will allow building detailed pharmacokinetic and pharmacodynamic models that will assist in design of our clinical studies. Project 5 will continue novel Phase l/ll trials to test ideas emanating from the preclinical projects. We will continue to optimize therapy with topotecan and irinotecan, and initiate trials of irinotecan with rapamycin. Our trials will explore novel anti-angiogenic therapies, and investigate the single agent activity of small molecule or antibody therapy targeted to the IGF-I receptor alone or combined with rapamycin. Our intent remains to advance preclinical information to the design of clinical trials, and extend these to cooperative groups.

描述（由申请人提供）：我们计划的主题仍然是基础实验室研究，动物模型评估和临床试验的整合，以开发儿童实体瘤的改进治疗。该计划密切关注新的和创新的方法，以改善细胞毒性疗法，并整合信号抑制剂与细胞毒性疗法。该计划的主题是实体瘤的发育治疗学，结合了细胞应激（生长因子信号缺氧，DNA损伤）如何影响实体瘤药物敏感性的基础研究。重点已放在识别的途径上游和下游的DNA损伤，可能是新的治疗目标，并在生长因子受体参与血管生成和细胞毒性药物治疗的细胞的生存。我们已经构建了该计划，以涵盖在此支持周期内可以实现的目标，以及实际上可能需要更长时间才能实现的目标，但这些目标可能代表了根治性治疗的全新方法。项目1继续IGF-IR/Akt/mTOR抑制剂的治疗研究，以及IGF-IR信号在儿童癌症中的作用。项目2扩展了已经证明mTOR信号传导调节细胞对DNA损伤的反应和突变频率的研究。项目3继续研究，证明未折叠蛋白反应（UPR）的激活调节细胞对细胞毒性药物的敏感性，并将在临床肿瘤中检查UPR激活。项目4将阐明抗血管生成药物如何调节细胞毒性药物（ABC转运蛋白）的药理学，并提供新的见解，以临床相关的方法来评估和监测肿瘤血管分布的特定变化，基于肿瘤血流/血管系统变化的非侵入性评估（通过MRI和超声检查）。这些研究将允许建立详细的药代动力学和药效学模型，这将有助于我们的临床研究的设计。项目5将继续进行新的I/II期试验，以测试临床前项目产生的想法。我们将继续优化拓扑替康和伊立替康的治疗，并启动伊立替康与雷帕霉素的试验。我们的试验将探索新的抗血管生成疗法，并研究针对IGF-I受体的小分子或抗体疗法单独或与雷帕霉素联合的单药活性。我们的目的仍然是推进临床前信息的临床试验的设计，并将其扩展到合作小组。