Signaling Drivers of Sarcoma Drug Resistance

项目摘要 肉瘤是一种异质性的罕见癌症，每年在美国影响约16，000人。骨 肉瘤特别罕见，每年诊断出3,500例。对治疗的抵抗是一个关键的临床 骨肉瘤管理的挑战，限制了全身治疗在骨肉瘤管理中的效用。 复发和转移性疾病。关于骨肉瘤先天性和获得性药物驱动因素的数据有限 阻力作为家长补助金的一部分，我们已经建立了一个管道，以发展个性化的骨肉瘤 类器官筛选数百种药物，并确定每个肿瘤的耐药性和敏感性。 我们将其与全基因组测序配对，以确定药物敏感性的突变相关性。在这里，我们将 通过在RNA和蛋白质水平上询问信号通路的中断来补充这项工作， 新辅助治疗前和后样本（Aim 1）以及不同转移性肿瘤中的耐药相关性 来自同一患者的病变（目标2）。空间和时间基因组学、转录组学和 蛋白质组学分析与功能性药物检测将使我们能够确定影响耐药性的因素 并开发出反应的生物标志物。

PROJECT SUMMARY Sarcomas are a heterogenous group of rare cancers affecting about 16,000 people each year in the US. Bone sarcomas are particularly rare, with 3,500 diagnoses a year. Resistance to therapy is a critical clinical challenge in bone sarcoma management, limiting the utility of systemic treatment in the management of relapsing and metastatic disease. There is limited data on drivers of bone sarcoma innate and acquired drug resistance. As part of the parent grant, 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 complement this work by interrogating disruptions in signaling pathways at the RNA and protein level to identify correlates of drug resistance in pre- and post-neoadjuvant samples (Aim 1) as well as in different metastatic lesions from the same patient (Aim 2). The combination of spatial and temporal genomic, transcriptomic and proteomic analyses with functional drug testing will allow us to determine the factors impacting drug resistance and develop biomarkers of response.