CLINICAL STUDIES

儿童高危实体瘤的治疗具有显著的发病率和复发或难治性 疾病仍然是这些儿童死亡的主要原因。需要新的治疗策略。这 项目5包括本计划项目资助的临床I/II期研究，重点是4 假设：（1）降低伊立替康给药毒性和增加其功效的方法， 说明托泊替康患者间变异性将进一步改善这些药物的功效，（2） 抑制mTOR信号传导将有效地减缓肿瘤生长，使肿瘤细胞对DMA损伤敏感 药物，并减少导致耐药性的药物诱导突变的发生率，（3）靶向 肿瘤源性VEGF与降低循环生长因子水平的协同作用将对 与仅靶向循环VEGF相比，抑制肿瘤血管生成，以及（4）与 IGF-I受体信号传导的抑制将增强客观反应。纳入选定的临床 试验将评估ErbB家族受体和BCRP/MRP以及mTOR的表达 抑制和恢复。每项临床试验均来自实验室项目的观察结果。目标1侧重于 继续开发喜树碱类药物， 在视网膜母细胞瘤中给予拓扑替康的方法以及口服头孢克肟和吉非替尼与 静脉内和口服伊立替康。在目标2中，我们将评估mTOR抑制剂CCI-779作为单一药剂， 雷帕霉素联合顺铂和伊立替康，定义毒性、潜在活性和替代 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的作用， 使用生物标志物的与托泊替康和与可用的mTOR抑制剂组合的肿瘤应答， 非侵入性成像最后，目标4将侧重于胰岛素样生长因子1型受体的评价 单独的IGF-1 R抑制剂和与mTOR抑制剂组合，定义毒性、药代动力学 参数、潜在活性和IGF-1 R下调的影响。这个临床项目是 在将关键实验室发现转化为儿童实体瘤治疗方法方面的基础 肿瘤，并为继续的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.