Novel Therapeutic Approaches for the Treatment of Rhabdomyosarcoma

横纹肌肉瘤（RMS）是儿童和青少年最常见的软组织肉瘤。 使用现代多模式治疗，超过75%的局限性RMS患者治愈 然而，复发性疾病患者的5年生存率仅为30%， 20多年来，结果没有明显改善。6年来，全面 RMS的基因组、表观基因组、蛋白质组和药物敏感性分析已经完成， 集成到中央数据库（iRDb）中。此外，多学科RMS翻译研究 已经组建了一个团队（RMS-TRT），使用iRDb来识别肿瘤的弱点， 治疗上的剥削已经确定了三种信号通路，它们似乎容易受到 新的分子靶向方案，在实验室研究中显示出希望。在这一提议中， 这些方案的综合临床前测试（例如，药代动力学，药效学， 成像和功效研究）来确定最有效的治疗。结果 这些研究的结果将用于设计圣裘德儿童研究中心的下一个RMS临床试验。 医院因此，能否成功地完成这里提出的目标将直接影响到人类的健康。 健康这项提案的一个独特和创新的方面是儿童实体瘤网络 （CSTN），一个网站（http：//www.stjude.org/CSTN/），通过该网站免费共享所有iRDb数据 与国际生物医学研究界没有合作的义务。大多数 通过数据中心提供的数据中有95%以上是未发布的，但所有这些数据都是共享的， 发现和推进儿科癌症的治疗。迄今为止，46名调查员提出了314项请求， 11个国家的机构已完成。我有一份将基础科学 将发现转化为临床试验，然后与国家和国际研究机构分享发现。 社区影响全球人类健康的最大变化。没有其他中锋拥有这支球队， 资源，专业知识，或工具，可用于执行这里提出的研究，并有效地移动 最有希望的发现直接用于临床试验。

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood and adolescence. Using contemporary multimodal therapies, more than 75% of patients with localized RMS are cured However, patients with recurrent disease experience 5-year survival rates of only 30%, and this outcome has not significantly improved in more than 20 years. Over the past 6 years, comprehensive genomic, epigenomic, proteomic, and drug-sensitivity profiling of RMS has been completed and integrated into a central database (iRDb). In addition, a multidisciplinary RMS translational research team (RMS-TRT) has been assembled to use the iRDb to identify tumor vulnerabilities that can be exploited therapeutically. Three signaling pathways have been identified that appear to be vulnerable to novel molecular-targeted regimens, which have shown promise in laboratory studies. In this proposal, comprehensive preclinical testing of those regimens (e.g., pharmacokinetics, pharmacodynamics, imaging and efficacy studies) will be performed to determine the most effective treatment. The results from these studies will be used to design the next RMS clinical trial at St. Jude Children's Research Hospital. Therefore, the successful completion of the Aims presented here will directly affect human health. One unique and innovative aspect of this proposal is the Childhood Solid Tumor Network (CSTN), a website (http://www.stjude.org/CSTN/) through which all of the iRDb data are shared freely with the international biomedical research community with no obligation to collaborate. The majority (>95%) of the data available through the CSTN is unpublished, but all of it is shared to accelerate discovery and advance cures for pediatric cancer. To date, 314 requests from 122 investigators at 46 institutions across 11 countries have been fulfilled. I have a proven record of moving basic science discoveries into clinical trials and then sharing findings with the national and international research communities to affect the greatest change in global human health. No other center has the team, resources, expertise, or tools available to perform the studies presented here and efficiently move the most promising findings directly into a clinical trial.