The Evolution of Sarcoma Drug Sensitivity through Time and Space

项目摘要 在美国，每年约有16，000人被诊断患有肉瘤。肉瘤是第三大 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3,500例，占所有癌症的0.2%。尽管进行了积极的治疗， 5-年生存率约为60%，转移性疾病的年生存率约为30%。 除了一线化疗之外，关于骨肉瘤药物敏感性的数据有限。与此同时，主要 我们对肉瘤分子标志和驱动因素的理解存在差距，可用的测序数据有限 在exome之外。重要的是，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 对于理解治疗反应和失败至关重要，仍然迫切需要将这些 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。 我们已经建立了一个开发个性化骨肉瘤类器官的管道，以筛选数百种药物 并确定每个肿瘤的耐药性和敏感性。我们把它和全基因组 测序以鉴定药物敏感性的突变相关性。在这里，我们将利用这条管道， 研究骨肉瘤的分子和药理学行为在单个患者体内的空间差异 (Aim 1）以及它们在从可治愈的原发性疾病向致命性转移性疾病过渡期间如何变化（目的2）。这 这项研究将使我们能够确定骨肉瘤转移是如何分化的，对治疗有何反应， 可操作的药物敏感性，以及创建一个详细的画像，如何骨肉瘤的发展下，治疗 选择性压力，与临床结果相关。

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.