PNET EXPERIMENTAL THERAPEUTICS--ANTINEOPLASTIC AGENTS AND TREATMENT DELIVERY

该项目进行实验室研究，以满足以下需求 髓母细胞瘤的有效新治疗策略 相关原始神经外胚层肿瘤(PNET)。这些研究 强调酪氨酸激酶生长因子作为靶点的作用 在PNET中进行治疗干预，并为 将对PNET神经生物学的新见解扩展到 临床环境。我们的主要重点将是新的治疗方法 软脑膜播散性PNETs。这一严重的临床 问题对治疗结果有深远的负面影响， 生死存亡。此外，治疗LM最有效的电流疗法是- PNET是颅脑脊髓放射治疗(RT)，它导致严重的 许多长期幸存者的认知障碍。鉴定 允许减少剂量的有效替代方案或 取消颅脑脊髓RT可能会延长持续时间 以及这些儿童的生存质量。我们的研究表明 鞘内(I.T.)细胞毒性药物的使用， 单抗、免疫毒素和重组毒素具有 与全身给药相比，具有特定的治疗优势。 因此，本项目将研究阿司匹林的疗效和毒性。 区域给药治疗LM-PNET的新药物。 在目标1中，我们将扩展我们对拓扑异构酶1(Topo 1)的研究 评价神经毒性和治疗效果的抑制剂 理工学院。TOPO-1抑制剂喜树碱在裸鼠体内的治疗 软脑膜MB大鼠模型。我们将通过以下方式扩大这些研究 探索潜在的协同互动，由我们的In确定 TOPO-1抑制剂和4-羟色胺的体外细胞毒性研究 羟基过氧环磷酰胺。在目标2中，我们将调查 重组假单胞菌外毒素的神经毒性和疗效 (PE)与酸性成纤维细胞生长因子融合，单独或在 联合转化生长因子α-PE，用于I.T. 软脑膜MB裸鼠模型的治疗。在目标3中，我们 将评估I.T.的神经毒性和疗效。雷帕霉素，一种 胰岛素样生长因子信号转导的抑制物 软脑膜MB模型。我们将在AIM扩展这些研究 4确定预测雷帕霉素敏感性的因素或 以MB为单位的抗性。我们预计，这些研究将扩大 PNET治疗策略的范围，并将适用于 其他儿童和成人脑肿瘤。

This Project pursues laboratory studies which address the need for effective new treatment strategies for medulloblastoma (MB) and related primitive neuroectodermal tumors (PNET). These studies emphasize the role of tyrosine kinase growth factors as targets for therapeutic intervention in PNET and establish a basis for extending new insights about the neurobiology of PNET into the clinical setting. Our primary focus will be new treatments for leptomeningeal (LM) dissemination of PNETs. This serious clinical problem has a profound negative effect on treatment outcome and survival. Moreover, the most effective current treatment for LM- PNET is craniospinal radiation therapy (RT), which causes severe cognitive impairment in many long-term survivors. Identification of effective alternatives which permit dose reduction or elimination of craniospinal RT is likely to improve the duration and quality of survival for these children. Our studies indicate that intrathecal (i.t.) administration of cytotoxic drugs, monoclonal antibodies, immunotoxins, and recombinant toxins has specific therapeutic advantages over systemic administration. Accordingly, this project will study the efficacy and toxicity of new agents administered regionally for the treatment of LM-PNET. In Aim 1, we will extend our studies of topoisomerase 1 (Topo 1) inhibitors to evaluate the neurotoxicity and therapeutic efficacy of i.t. treatment with camptothecin, a Topo 1 inhibitor, in a nude rat model of leptomeningeal MB. We will expand these studies by exploring potential synergistic interactions, identified by our in vitro cytotoxicity studies, between Topo 1 inhibitors and 4- hydroperoxy-cyclophosphamide. In Aim 2, we will investigate the neurotoxicity and efficacy of recombinant Pseudomonas exotoxin (PE) fused with acidic fibroblast growth factor, alone or in combination with transforming growth factor alpha-PE, for i.t. treatment in a nude rat model of leptomeningeal MB. In Aim 3, we will evaluate the neurotoxicity and efficacy of i.t. rapamycin, an inhibitor of insulin-like growth factor signal transduction, in a model of leptomeningeal MB. We will extend these studies in Aim 4 to identify factors which predict rapamycin sensitivity or resistance in MB. We anticipate that these studies will broaden the scope of PNET therapeutic strategies and will be applicable to other childhood and adult brain tumors.