Development

实体瘤开发治疗计划（DTSMP）的核心作用是： 改善儿童和青少年实体瘤治愈性治疗。促进了这一目标 通过多学科转化研究，重点是确定新的治疗靶点， 了解儿童实体瘤的生长调节，药物作用机制，耐药性， 诊断和临床治疗。该方案由41名成员组成（27名主要任命，14名 与二级任命）代表11个学术部门圣裘德。我们的临床前研究 从开发高通量筛选到鉴定新的药理学探针， 目标，基于机制的研究，使用遗传上易处理的生物体，如酵母，用于鉴定药物 靶点，以及与细胞毒性剂相关的损伤DMA的修复过程。哺乳动物研究 细胞涉及体外培养以确定药物靶点以及获得性和内在抗性的机制。 体内模型包括代表儿童和青少年常见实体瘤的异种移植物组， 以及其他项目合作者制作的转基因模型。该计划富有成效， 超过390篇论文（88篇内部论文，85篇跨项目论文），并拥有超过620万美元的同行评审赠款资金 支持主要方案成员。 该计划不断促进分子生物学基础实验室研究之间的相互作用， 药理学、药代动力学和临床研究，为临床I/II期的设计和实施提供信息 审判在过去的资助期间，该计划开发了治疗高风险的新方案。 实体瘤如晚期神经母细胞瘤、横纹肌肉瘤、复发性肾母细胞瘤和脑 肿瘤的此外，我们对喜树碱、雷帕霉素类似物和其他新药物的研究也取得了进展。 我们对如何更好地在儿童中使用这些药物的理解。这些协议源自 项目内的基础研究。此外，十个圣裘德协议已扩展到国家 儿童肿瘤组（COG）的临床试验。来自临床试验的信息允许进一步开发 和临床前研究的完善，最终导致改进的治疗。临床前和临床 研究将建立在目前的工作与DMA拓扑异构酶I抑制剂，雷帕霉素，并开始小 分子筛我们将继续鉴定赋予耐药性的基因，并评估这些药物。 特定细胞信号通路的抑制剂。概述的研究将开发新的抗血管生成药物 用于治疗高危神经母细胞瘤和肉瘤的肿瘤选择性疗法的方法。

The Developmental Therapeutics for Solid Malignancies Program (DTSMP) has as its central role the improvement in curative therapy for children and adolescents with solid tumors. This objective is facilitated through multidisciplinary translational research, focusing on the identification of novel targets for therapy, understanding growth regulation of childhood solid tumors, mechanisms of drug action, drug resistance, diagnosis and clinical therapy. The program comprises 41 members (27 with primary appointments and 14 with secondary appointments) representing 11 academic departments St. Jude. Our preclinical studies range from development of high throughput screening to identify novel pharmacological probes to validate targets, mechanism based studies using genetically tractable organisms such as yeast for identifying drug targets, and repair processes associated with cytotoxic agents that damage DMA. Studies in mammalian cells involve in vitro culture to determine drug targets, and mechanisms of acquired and intrinsic resistance. In vivo models include panels of xenografts that represent common solid tumors in children and adolescents, and transgenic models produced by collaborators in other programs. The program has been productive with over 390 papers (88 intra-, 85 inter-programmatic), and has over $6.2 million in peer-reviewed grant funding supporting primary program members. The Program has continually fostered interactions among the basic laboratory investigations in molecular pharmacology, pharmacokinetics and clinical research to inform the design and conduct of clinical Phase l/ll trials. Over the past period of funding, the program has developed novel protocols for treatment of high-risk solid tumors such as advanced neuroblastoma, rhabdomyosarcoma, relapsed Wilms tumor and brain tumors. In addition, our studies with the camptothecins, the rapalogs, and other new agents have furthered our understanding on how better to use these agents in children. These protocols have been derived from fundamental studies within the program. In addition, ten St. Jude protocols have been extended to national trials in the Children's Oncology Group (COG). Information from the clinical trials allows further development and refinement of the preclinical research, leading ultimately to improved therapy. Preclinical and clinical studies will build on the current work with DMA topoisomerase I inhibitors, rapamycins, and start small molecule screens. We will continue to identify genes conferring drug resistance, and evaluate these agents with inhibitors of specific cellular signaling pathways. Studies outlined will develop novel anti-angiogenic approaches to tumor-selective therapy for treatment of high-risk neuroblastoma, and sarcomas.