CLINICAL STUDIES

儿童高危实体瘤的治疗有显著的发病率和复发或难治性。 疾病仍然是这些儿童的主要死亡原因。需要新的治疗策略。这 项目5包括本计划项目资助的临床L/11期研究，重点为 假设：(1)伊立替康的减毒增效途径 说明拓扑替康的患者间变异性将进一步提高这些药物的疗效，(2) 抑制mTOR信号将有效减缓肿瘤生长，使肿瘤细胞对DMA损伤敏感 药物，并降低导致耐药性的药物诱导突变的比率，(3)靶向 肿瘤来源的血管内皮生长因子与循环生长因子水平的降低将对 肿瘤血管生成优于仅靶向循环血管内皮生长因子和(4)抑制mTOR与联合应用 抑制IGF-I受体信号转导将增强客观反应。合并到选定的临床 试验将评估ErbB受体家族和BCRP/MRP的表达，以及mTOR 抑制和恢复。每一项临床试验都是从实验室项目的观察中得出的。目标1重点 论喜树碱的可持续发展与药动学靶向性评价 拓扑替康治疗视网膜母细胞瘤的剂量探讨及口服头孢克辛和吉非替尼联合应用 静脉和口服伊立替康。在目标2中，我们将评估mTOR抑制剂CCI-779作为单一药物和 雷帕霉素与顺铂和伊立替康联合应用，确定毒性、潜在活性和替代物 肿瘤反应的标志物。在目标3中，我们将评估贝伐单抗对肿瘤血管和血管的影响。 使用生物标记物和mTOR抑制剂联合使用拓扑替康和可用mTOR抑制剂的肿瘤反应 非侵入性成像。最后，目标4将重点评估胰岛素样生长因子1型受体 (IGF-1R)抑制剂单独和与mTOR抑制剂联合使用，定义毒性、药代动力学 IGF-1R的参数、潜在活性和下调的影响这一临床项目是 将关键的实验室发现转化为治疗儿童固体中毒的基本方法 并为继续进行实验室研究提供方向。

The treatment of children with high-risk solid tumors has significant morbidity and relapse or refractory disease still is the leading cause of death in these children. New therapeutic strategies are needed. This project 5 comprises the clinical Phase l/ll research studies of this Program Project Grant and focuses on 4 hypotheses: (1) that approaches to decrease toxicity and increase efficacy of irinotecan administration and that account for interpatient variability of topotecan will further improve efficacy of these agents, (2) that inhibition of mTOR signaling will effectively slow tumor growth, sensitize tumor cells to DMA damaging agents, and reduce the rate of drug induced mutations that contribute to drug resistance, (3) that targeting tumor-derived VEGF in concert with reducing levels of circulating growth factor will have greater effect on tumor angiogenesis than targeting only circulating VEGF and (4) that inhibition of mTOR in combination with inhibition of IGF-I receptor signaling will enhance objective responses. Incorporated into selected clinical trials will be assessments of the expression of the ErbB family of receptors and BCRP/MRP, and mTOR inhibition and recovery. Each clinical trial is derived from observations in laboratory projects. Aim 1 focuses on the continued development of camptothecins with the evaluation of pharmacokinetically targeted approach to dosing topotecan in retinoblastoma and the use of oral cefixime and gefitinib in combination with intravenous and oral irinotecan. In Aim 2 we will evaluate the mTOR inhibitor CCI-779 as a single agent and rapamycin in combination with cisplatin and irinotecan, defining toxicity, potential activity and surrogate markers of tumor response. In Aim 3 we will evaluate the effect of bevacizumab on tumor vasculature and tumor response in combination with topotecan and with an available mTOR inhibitor using biomarkers and noninvasive imaging. Lastly, Aim 4 will focus on the evaluation of insulin-like growth factor type -1 receptor (IGF-1 R) inhibitors alone and in combination with an mTOR inhibitor, defining toxicity, pharmacokinetic parameters, potential activity and the effects of downregulation of IGF-1 R. This clinical project is fundamental in translating key laboratory discoveries into the treatment approaches for children with solid tumors and providing direction for continued laboratory investigations.