Studies of Childhood Solid Tumors

儿童实体瘤的研究

• 批准号: 7668525
• 负责人: Linda M Hendershot
• 金额: $ 225.84万
• 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/7668525
• 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）：我们项目的主题仍然是整合基础实验室研究、动物模型评估和临床试验，以开发改进的儿童实体瘤治疗方法。该计划密切关注改善细胞毒性治疗以及将信号抑制剂与细胞毒性治疗相结合的新方法和创新方法。该项目的主题是实体瘤的发育治疗，纳入了细胞应激（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。重点是鉴定可能成为新疗法目标的 DNA 损伤上游和下游途径，以及参与血管生成和细胞毒性药物处理细胞存活的生长因子受体。我们制定了该计划，以涵盖在该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，但这可能代表了全新的治疗方法。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 扩展了已证明 mTOR 信号传导调节细胞对 DNA 损伤和突变频率的反应的研究。项目 3 继续进行研究，证明未折叠蛋白反应 (UPR) 的激活可调节细胞对细胞毒性药物的敏感性，并将检查临床肿瘤中的 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，并基于对肿瘤血流/脉管系统变化的无创评估（通过 MRI 和超声检查），为评估和监测肿瘤血管分布的特定变化的临床相关方法提供新的见解。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 将继续进行新颖的 I/II 期试验，以测试临床前项目的想法。我们将继续优化拓扑替康和伊立替康的治疗，并启动伊立替康联合雷帕霉素的试验。我们的试验将探索新型抗血管生成疗法，并研究单独针对 IGF-I 受体或与雷帕霉素联合的小分子或抗体疗法的单药活性。我们的目的仍然是将临床前信息推进临床试验的设计，并将其扩展到合作团体。