Development

实体恶性肿瘤的发展治疗计划(DTSMP)作为其核心作用 改善儿童和青少年实体瘤的治疗方法。这一目标是有帮助的 通过多学科的转化性研究，重点确定新的治疗目标， 了解儿童实体瘤的生长规律，药物作用机制，耐药性， 诊断和临床治疗。该计划有41名成员(27名有主要任命，14名 与二级任命)代表圣犹大11个学术部门。我们的临床前研究 范围从高通量筛选的开发到识别新的药理探针以验证 利用酵母菌等可遗传生物识别药物的靶点、机制研究 与破坏DMA的细胞毒剂相关的目标和修复过程。哺乳动物的研究 细胞涉及体外培养，以确定药物靶点，以及获得性和内在耐药的机制。 活体模型包括代表儿童和青少年常见实体肿瘤的异种移植物面板， 以及其他项目合作者生产的转基因模型。该计划已经取得了丰硕的成果 超过390篇论文(88篇是计划内的，85篇是计划间的)，并有超过620万美元的同行评审赠款资金 支持主要计划成员。 该计划不断促进分子科学基础实验室研究之间的相互作用 药理、药代动力学和临床研究为L/11临床阶段的设计和实施提供信息 审判。在过去的一段时间里，该项目开发了治疗高风险患者的新方案 实体瘤，如晚期神经母细胞瘤、横纹肌肉瘤、复发性Wilms瘤和脑 肿瘤。此外，我们对喜树碱、拉帕罗格和其他新制剂的研究进一步深入。 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 该计划内的基础研究。此外，圣犹大的十项议定书已扩展到国家 儿童肿瘤学小组(COG)的试验。来自临床试验的信息使进一步发展成为可能 以及对临床前研究的改进，最终导致治疗的改进。临床前和临床 研究将建立在目前对DMA拓扑异构酶I抑制剂雷帕霉素的研究基础上，并从小规模开始 分子屏蔽物。我们将继续识别与耐药性有关的基因，并对这些药物进行评估 使用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 肿瘤选择性治疗高危神经母细胞瘤和肉瘤的方法。

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.