CLINICAL STUDIES

临床研究

• 批准号: 8309815
• 负责人: Victor M. Santana
• 金额: $ 20.74万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309815
• 关键词: Accounting; Apoptosis; Biochemical Markers; Biological Availability; Biological Markers; CCI-779; Camptothecin; Cause of Death; Cefixime; Child; Childhood Solid Neoplasm; Cisplatin; Clinical; Clinical Trials; Cytotoxic agent; DNA Damage; Decontamination; Development; Dose; Down-Regulation; Drug Kinetics; Drug resistance; ErbB Receptor Family Protein; Evaluation; Gefitinib; Glioma; Growth Factor; Image; Induced Mutation; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Intestines; Intravenous; Investigation; Laboratories; Morbidity - disease rate; Neuroblastoma; Newly Diagnosed; Oral; Pharmaceutical Preparations; Phase; Program Research Project Grants; Receptor Signaling; Recovery; Recurrent disease; Reducing Agents; Refractory; Refractory Disease; Relapse; Retinoblastoma; Rhabdomyosarcoma; SDZ RAD; Schedule; Signal Transduction; Sirolimus; Solid Neoplasm; Surrogate Markers; Topotecan; Toxic effect; Translating; Tumor Angiogenesis; Tumor-Derived; Vascular Endothelial Growth Factors; Vincristine; activity marker; analog; bevacizumab; high risk; improved; inhibitor/antagonist; irinotecan; mTOR Inhibitor; mTOR inhibition; neoplastic cell; novel therapeutics; research study; response; tumor; tumor growth

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.

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