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（MB）的有效新治疗策略， 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 为PNET的治疗干预奠定基础， 将关于PNET神经生物学的新见解扩展到 临床设置。 我们的主要重点将是新的治疗方法， 脑膜炎的软脑膜（LM）传播。 这一严重的临床 问题对治疗结果有深刻的负面影响， 生存 此外，目前治疗LM最有效的方法- PNET是颅脊髓放射治疗（RT）， 许多长期幸存者的认知障碍。 识别 允许减少剂量的有效替代品，或 消除颅脊髓RT可能会改善持续时间 和生存质量。 我们的研究表明 鞘内（i.t.）给予细胞毒性药物， 单克隆抗体、免疫毒素和重组毒素， 与全身给药相比具有特定的治疗优势。 因此，本项目将研究 区域性给药治疗LM-PNET的新药物。 在目标1中，我们将扩展对拓扑异构酶1（Topo 1）的研究 抑制剂，以评价神经毒性和治疗效果 在I.T.喜树碱，一种拓扑异构酶1抑制剂，在裸 大鼠软脑膜MB模型 我们将扩大这些研究， 探索潜在的协同作用，我们在 Topo 1抑制剂和4- 过氧化氢环磷酰胺。 在目标2中，我们将研究 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 与转化生长因子α-PE的组合，用于i.t. 在软脑膜MB的裸大鼠模型中的治疗。 在目标3中， 将评估i.t.的神经毒性和疗效。雷帕霉素 胰岛素样生长因子信号转导抑制剂， 软脑膜MB模型。 我们将在Aim中扩展这些研究 4确定预测雷帕霉素敏感性的因素， MB中的电阻。 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.