Project 1: Optimization of therapeutic approaches for children with relapsed sarcomas using precision medicine.

在确诊患有实体瘤的儿童中，约30%将死于复发性和难治性疾病。 因此，发现和实施创新的治疗方法，最大限度地减少不良反应， 治疗相关的副作用是关键的未满足的临床需求。我们的多学科团队包括 临床、生物信息学和基础研究人员正在寻求一种基于精确医学的方法， 将来，可以实现改善复发性和难治性疾病儿童的治疗结果。我们 长期目标是通过利用精确医学方法优化癌症儿童的治疗 基于对肿瘤和生殖细胞基因组的评估，以指导个体化治疗。在这一努力中，双方 对侵袭性儿童癌症进行集中和全面的深度测序， 将进行药物基因组学研究。本提案的目的是为建立一个 循证策略，为复发性乳腺癌儿童制定精确的药物治疗方案 恶性肿瘤。随着基因组测序能力的效率和质量的快速提高， 综合测序方法，对个体癌症进行基因组表征，为治疗决策提供信息- 对于患有侵袭性的，通常是致命的恶性肿瘤的儿童来说是可行的。与临床部分并行 该项目的一部分是对患者来源的细胞系和临床前异种移植模型进行基于实验室的评价 从同一患者群体中开发出来的药物将允许对潜在的治疗选择进行更广泛的评估 以及通过全面的"组学"研究发现新的靶点。我们的方法还提供了一个 创新的机会，以确定个性化的，治愈性的治疗，我们的一些最顽固的儿科 疾病该项目中提出的研究在多个层面上都是创新的，这不仅对我们的 儿科癌症精准医疗计划以及各地的儿科患者。儿科癌症 精确医学在开发快速准确的基因组分析管道方面处于起步阶段 然后是关于基因组导向治疗方案的团队决定。我们的多学科项目 旨在为癌症儿童提供最先进的个性化治疗建议， 下一个治疗决定的时间是至关重要的。这项研究的总体影响是深远的，在改善 癌症复发儿童目前的选择有限。从这些研究中获得的信息将 通过为医生提供关键信息，使其做出明智的决定， 更安全、更有效地为儿童使用药物。这些多学科研究的直接结果将是 发现新的生物标志物和预测特征，这将提高终身治疗的精确性- 威胁儿童癌症，并尽量减少不良的治疗相关的副作用。

In children diagnosed with solid tumors, approximately 30% will die due to relapsed and refractory disease. Therefore the discovery and implementation of innovative approaches to therapy that minimize undesirable treatment-associated side effects are a critical unmet clinical need. Our multidisciplinary team comprised of clinical, bioinformatics, and basic researchers are pursuing a precision medicine-based approach so that in the future, improved treatment outcomes for children with relapsed and refractory disease can be realized. Our long-range goal is to optimize treatment of children with cancer by utilizing a precision medicine approach based on evaluation of the tumor and germline genomes to guide individualized therapies. In this effort, both focused and comprehensive deep sequencing of aggressive childhood cancers together with focused germline pharmacogenomics will be conducted. The objective of this proposal is to develop the foundation for an evidence-based strategy for developing precision medicine treatment regimens for children with relapsed malignancies. With the rapid improvement in efficiency and quality of genomic sequencing capabilities, an integrative sequencing approach to genomically characterize individual cancers to inform therapeutic decision- making for children with aggressive, often fatal malignancies is feasible. In parallel with the clinical component of this project, laboratory-based evaluation of patient-derived cell lines, and preclinical xenograft models developed from this same population of patients will allow broader evaluation of potential therapeutic options as well as discovery of novel targets via a comprehensive `omic' investigation. Our approach also provides an innovative opportunity to identify personalized, curative therapies for some of our most recalcitrant pediatric diseases. The research proposed in this project is innovative at the multiple levels critical not only for our pediatric cancer precision medicine program as well as pediatric patients everywhere. Pediatric cancer precision medicine is in its infancy in terms of developing a pipeline for rapid and accurate genomic analysis followed by team-based decisions regarding genome-directed therapeutic options. Our multidisciplinary project aims to provide cutting-edge, individualized therapeutic recommendations for children with cancer, for whom time to next therapeutic decision is crucial. The overall impact of this research is far reaching in improving the limited options that children with relapse cancers currently have. Information gained from these studies will have a significant positive impact by providing critical information for physicians to make informed decisions for safer and more effective use of drugs in children. The direct outcome of these multidisciplinary studies will be discovery of new biomarkers and predictive signatures that will increase the precision of treatment for life- threatening childhood cancers and minimize undesirable treatment-associated side effects.