PNET EXPERIMENTAL THERAPEUTIC--NEW ANTINEOPLASTIC AGENTS AND DRUG DELIVERY

寻找新的抗肿瘤药物用于原始肿瘤治疗的研究 神经外胚层肿瘤(PNET)是根据PNETs的敏感性而被证明是合理的 向各种药物疗法展示，临床前实验室的成功 预测PNET临床反应的研究，以及PNET的持久性 尽管进行了密集的辅助治疗，治疗还是失败了。评估新功能 局部和软脑膜(CSF)肿瘤控制问题的探讨 我们建议进行两类新的临床前实验室研究 抗肿瘤药物：(1)转化生长因子-α-假单胞菌 外毒素(转化生长因子-α-PE)，是一种重组毒素，其中转化生长因子-α， 表皮生长因子受体底物，与一种基因融合 修饰的假单胞菌外毒素；(2)拓扑异构酶I抑制剂，包括 喜树碱、拓扑替康和其他新开发的类似物。这些特工 在脑瘤治疗方面有潜在的优势，但还没有 系统评估。在目标1中，我们将评估其毒性， 鞘内注射转化生长因子-α-PE治疗慢性阻塞性肺疾病的药理和疗效 PNET软脑膜转移。我们将采用相同的研究设计 我们用来开发鞘内4-羟基过氧环磷酰胺 目前的I期临床试验。在目标2中，我们将研究其毒性和 转化生长因子-α-聚乙烯复合缓释生物降解剂的疗效观察 用于治疗局部颅内肿瘤的聚合物。这些 调查表明，与亨利·布雷姆博士继续合作 (约翰霍普金斯大学)关于这一创新方法的应用 到脑瘤的局部药物输送。目标3和目标4将评估 拓扑异构酶I抑制剂在PNET治疗中的潜在用途和意愿 解决临床前生化检测和鉴定问题 对这些药物反应的预测指标。我们预计这些研究 会对其他儿童和成人的治疗具有广泛的适用性 原发脑瘤。

Studies to identify new antineoplastic agents for clinical use in primitive neuroectodermal tumors (PNET) are justified by the sensitivity PNETs have shown to various drug therapies, the success of preclinical laboratory studies in predicting PNET clinical response, and the persistence of treatment failures despite intensive adjuvant regimens. To evaluate new approaches to the problems of local and leptomeningeal (CSF) tumor control, we propose preclinical laboratory studies of two classes of new antineoplastic agents: (1) Transforming Growth Factor-alpha-pseudomonas exotoxin (TGF-alpha-PE), a recombinant toxin in which TGF-alpha, the epidermal growth factor receptor substrate, is fused with a genetically modified pseudomonas exotoxin; (2) Topoisomerase I inhibitors, including camptothecin, topotecan and other newly developed analogs. These agents have potential advantages for brain tumor therapy that have not been systematically evaluated. In Aim 1, we will evaluate the toxicity, pharmacology and efficacy of intrathecal TGF-alpha-PE for the treatment of PNET leptomeningeal metastases. We will employ the same research design that we used to develop intrathecal 4-hydroperoxy-cyclophosphamide for current phase I clinical trials. In Aim 2, we will study the toxicity and efficacy of TGF-alpha-PE incorporated into sustained-release biodegradable polymers for the treatment of local intracranial tumors. These investigations represent a continued collaboration with Dr. Henry Brem (Johns Hopkins University) on the application of this innovative approach to local drug delivery in brain tumors. Aims 3 and 4 will evaluate the potential use of topoisomerase I inhibitors for PNET therapy and will address the preclinical testing and identification of biochemical predictors of response to these agents. We anticipate that these studies will have broad applicability to the treatment of other childhood and adult primary brain tumors.