PHASE I & II STUDIES IN CHILDREN WITH SOLID TUMORS

描述（由申请人提供）：尽管当代治疗策略已改善实体瘤儿童的生存率，但复发或难治性疾病仍是这些儿童死亡的主要原因。需要新的治疗策略，并进一步了解控制肿瘤增殖，分化和细胞死亡的生物学和生物化学过程，以了解如何将有前途的新化疗和生物制剂纳入治疗方案。该项目10包括本项目资助的临床I/II期研究，并侧重于3个假设：（1）雷帕霉素类似物CCI-779将抑制信号转导分子mTOR（雷帕霉素的靶点）并延缓儿科肿瘤的生长;（2）ErbB 1信号传导抑制剂（ZD 1839）联合静脉注射喜树碱将在患有神经母细胞瘤和高级别胶质瘤的儿童中产生有临床意义的反应，在表达该受体肿瘤（胶质母细胞瘤）中抑制ErbB 1或通过调节ABC转运蛋白如神经母细胞瘤中的BCRP和MRP;和（3）4-苯胺基喹唑酮如ZD 1839可调节口服喜树碱的生物利用度，并导致与临床前异种移植模型中的反应相关的全身暴露。纳入选定的临床试验将评估ErbB家族受体和BCRP/MRP的表达，以及mTOR抑制和恢复。每项临床试验均来自实验室项目的观察结果。具体目标1侧重于评价CCI-779作为单一药剂或组合，定义毒性、潜在活性和肿瘤反应标志物。在特定 目的2和3，我们将评价口服ZD 1839联合静脉或口服喜树碱，定义MTD、生物利用度和肿瘤缓解。最后，具体目标4将侧重于继续评价拓扑替康给药治疗复发性肾母细胞瘤的药代动力学靶向方法以及喜树碱与DNA损伤剂的联合研究。该临床项目是将关键实验室发现转化为儿童实体瘤治疗方法的基础，并为持续的实验室研究提供方向。

DESCRIPTION (provided by applicant): Although contemporary treatment strategies have improved the survival of children with solid tumors, relapse or refractory disease still accounts for the leading cause of death in these children. New therapeutic strategies are needed and a further understanding of the biologic and biochemical processes that control tumor proliferation, differentiation and cell death to provide insights into how promising new chemotherapeutic and biologic agents can be incorporated into treatment regimens. This Project 10 comprises the clinical Phase I/II research studies of this Program Project Grant and focuses on 3 hypotheses: (1) that the rapamycin analogue CCI-779 will inhibit the signal transduction molecule mTOR (target of rapamycin) and retard the growth of pediatric tumors; (2) that an inhibitor of ErbB1 signaling (ZD1839) in combination with intravenous camptothecins will produce clinically meaningful responses in children with neuroblastoma and highgrade gliomas either through direct inhibition of ErbB1 in tumors expressing this receptor (glioblastomas) or through modulating ABC transporters such as BCRP and MRP in neuroblastoma; and (3) that 4-anilinoquinazolones such as ZD1839 may modulate the bioavailability of oral camptothecins and result in systemic exposures associated with response in pre-clinical xenograft models. 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. Specific aim 1 focuses on evaluation of CCI-779 as a single agent or in combination defining toxicity, potential activity and markers of tumor response. In Specific aims 2 and 3, we will evaluate oral ZD1839 in combination with intravenous or oral camptothecins defining the MTD, bioavailability and tumor responses. Lastly, Specific aim 4 will focus on continued evaluation of a pharmacokinetically targeted approach to dosing of topotecan for relapsed Wilms tumor and combination studies of camptothecins with DNA damaging agents. 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.