The Evolution of Sarcoma Drug Sensitivity through Time and Space

项目总结 在美国，每年约有16,000人被诊断为肉瘤。肉瘤排在第三位 影响儿童的常见癌症约占所有诊断的儿童肿瘤的15%。骨肿瘤是 最罕见的是，每年不到3500例，占所有癌症的0.2%。尽管接受了积极的治疗，但总的来说 5年生存率约为60%，转移性疾病约为30%。 除了一线化疗外，关于骨肉瘤药物敏感性的数据有限。同时，还有主要的 我们对肉瘤分子特征和驱动因素的理解存在差距，现有的测序数据有限 在序曲之外。关键的是，很少有肉瘤进行了全基因组测序、纵向分析或 多区域测序以了解它们的空间和时间基因组变异性。这种可变性被认为是 对理解治疗反应和失败至关重要，仍然迫切需要将它们联系起来 在大多数肿瘤类型中，从分子特征到药物敏感性的定量方面。 我们已经建立了一条开发个性化骨肉瘤有机化合物的管道，以筛选数百种药物 并确定每个肿瘤的耐药性和敏感性曲线。我们将其与全基因组配对 测序以确定药物敏感性的突变相关因素。在这里，我们将利用这条管道来 研究单个患者骨肉瘤的分子和药理学行为在空间上的差异 (目标1)以及它们在从可治愈的原发疾病向致命转移性疾病的转变过程中如何变化(目标2)。这 研究将使我们能够确定骨肉瘤转移是如何分化和对治疗做出反应的，并确定 可操作的药物敏感性，以及创建骨肉瘤如何在治疗下演变的详细描述 选择性压力，与临床结果有关。

PROJECT SUMMARY Approximately 16,000 people are diagnosed with sarcoma each year in the US. Sarcomas are the third most common cancer affecting children constituting about 15% of all diagnosed childhood tumors. Bone tumors are the rarest of all, with less than 3,500 cases a year or 0.2% of all cancers. Despite aggressive treatment, overall 5-year survival rates are ~60% and around 30% for metastatic disease. There is limited data on bone sarcoma drug sensitivity beyond first line chemotherapy. In parallel, there are major gaps in our understanding of sarcomas molecular hallmarks and drivers, with limited sequencing data available beyond the exome. Critically, very few sarcomas have had whole-genome sequencing, longitudinal profiling or multi-region sequencing to understand their spatio- and temporal-genomic variability. This variability is thought to be critical to understanding treatment response and failure, and there remains an urgent need to relate these molecular features to quantitative aspects of drug sensitivity in most tumor types. We have established a pipeline to develop personalized bone sarcoma organoids to screen hundreds of drugs and determine a drug resistance and sensitivity profile for each tumor. We pair this with whole-genome sequencing to identify mutational correlates of drug sensitivity. Here we will take advantage of this pipeline to study how the molecular and pharmacologic behavior of bone sarcomas differs spatially within a single patient (Aim 1) and how they vary during their transition from curable primary to lethal metastatic disease (Aim 2). This study will allow us to define how bone sarcoma metastases diverge and respond to therapy and identify actionable drug sensitivities as well as create a detailed portrait of how bone sarcomas evolve under therapeutic selective pressure, linked to clinical outcomes.