PNET EXPERIMENTAL THERAPEUTIC--NEW ANTINEOPLASTIC AGENTS AND DRUG DELIVERY

研究以确定用于临床的新的抗肿瘤药物， 神经外胚层肿瘤（PNET）是合理的敏感性PNET有 各种药物治疗的成功，临床前实验室 预测PNET临床反应的研究，以及 尽管有强化辅助治疗方案，但治疗失败。 评估新 解决局部和软脑膜（CSF）肿瘤控制问题的方法， 我们提出了两类新的临床前实验室研究 抗肿瘤剂：（1）转化生长因子-α-假丝酵母 外毒素（TGF-α-PE），一种重组毒素，其中TGF-α， 表皮生长因子受体底物，与基因融合， （2）拓扑异构酶I抑制剂，包括 喜树碱、拓扑替康和其它新开发的类似物。 这些试剂 具有脑肿瘤治疗的潜在优势， 系统评价。 在目标1中，我们将评估毒性， 鞘内注射TGF-α-PE治疗糖尿病的药理学和疗效 PNET软脑膜转移。 我们将采用相同的研究设计 我们用来开发鞘内注射4-过氧化氢环磷酰胺 I期临床试验。 在目标2中，我们将研究毒性， TGF-α-PE掺入缓释生物可降解材料的功效 用于治疗局部颅内肿瘤的聚合物。 这些 研究代表了与亨利布雷姆博士的持续合作 （约翰霍普金斯大学）对这种创新方法的应用 to local局部drug药物delivery交付in brain脑tumors肿瘤. 目标3和4将评估 拓扑异构酶I抑制剂用于PNET治疗的潜在用途， 解决临床前测试和生化鉴定 预测对这些药物的反应。 我们预计这些研究 将具有广泛的适用性，以治疗其他儿童和成人 原发性脑肿瘤

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.