Studies of Childhood Solid Tumors

描述(由申请人提供)：我们计划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。该计划密切关注改进细胞毒治疗的新的和创新的方法，并将信号抑制剂与细胞毒治疗相结合。该项目的主题是实体肿瘤的发育疗法，包括关于细胞应激(生长因子信号缺氧、DNA损伤)如何影响实体肿瘤药物敏感性的基础研究。重点放在识别DNA损伤的上游和下游可能成为新治疗目标的途径，以及参与血管生成和细胞毒剂处理的细胞存活的生长因子受体。我们已经构建了这个计划，包括在这个支持周期内可以实现的目标，以及现实中可能需要更长时间才能实现的目标，但这可能代表着根本性的治疗方法。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扩展了已经证明mTOR信号调节细胞对DNA损伤的反应和突变频率的研究。项目3继续进行研究，证明未折叠蛋白反应(UPR)的激活调节细胞对细胞毒剂的敏感性，并将检查临床肿瘤中UPR的激活。项目4将阐明抗血管生成药物如何调节细胞毒剂(ABC转运体)的药理学，并为临床相关方法提供新的见解，以基于对肿瘤血流/血管系统变化的非侵入性评估(通过核磁共振和超声)来评估和监测肿瘤血管的特定变化。这些研究将允许建立详细的药代动力学和药效学模型，这将有助于我们临床研究的设计。项目5将继续进行新的L/11期试验，以测试源自临床前项目的想法。我们将继续优化拓扑替康和伊立替康的治疗，并启动伊立替康与雷帕霉素的联合试验。我们的试验将探索新的抗血管生成疗法，并调查针对IGF-I受体的小分子或抗体疗法或与雷帕霉素联合治疗的单剂活性。我们的意图仍然是将临床前信息推进到临床试验的设计中，并将这些扩展到合作小组。

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.