The Evolution of Sarcoma Drug Sensitivity through Time and Space

肉瘤药物敏感性随时间和空间的演变

• 批准号: 10202513
• 负责人: Paul Christopher Boutros
• 金额: $ 49.69万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10202513
• 关键词: Affect; Architecture; Behavior; Biological Models; Biopsy; Bone neoplasms; Cell Line; Cessation of life; Child; Clinical; Clinical Trials; Connective and Soft Tissue; Cytotoxic Chemotherapy; Data; Diagnosis; Disease; Drug Screening; Drug resistance; Evolution; Genomics; Histologic; Life; Link; Lung; Lung nodule; Malignant Neoplasms; Metastatic Neoplasm to the Lung; Modeling; Molecular; Mutation; Neoadjuvant Therapy; Neoplasm Metastasis; Newly Diagnosed; Operative Surgical Procedures; Organoids; Outcome; Patients; Pediatric Neoplasm; Pharmaceutical Preparations; Pharmacology; Population; Portraits; Primary Neoplasm; Relapse; Resistance; Sampling; Specimen; Structure; Survival Rate; System; Techniques; Technology; Testing; Therapeutic; Time; Tissue Sample; Treatment Failure; Tumor Subtype; aggressive therapy; bone; cancer diagnosis; chemotherapy; driver mutation; drug sensitivity; exome; genome sequencing; improved; model development; osteosarcoma; pressure; rare cancer; reconstruction; response; sarcoma; screening; targeted treatment; therapeutic development; therapy resistant; treatment response; tumor; whole genome

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.

项目摘要 在美国，每年约有16,000人被诊断出患有肉瘤。肉瘤是第三个 影响儿童的常见癌症占所有被诊断的儿童肿瘤的15％。骨肿瘤是 最罕见的是，每年不到3500例，占所有癌症的0.2％。尽管有积极的治疗，总体 转移性疾病的5年生存率约为60％，约30％。 超出一线化学疗法以外的骨肉瘤药物敏感性的数据有限。并行，有专业 我们对肉瘤分子标志和驱动因素的理解的差距，可用的测序数据有限 超越外显子。至关重要的是，很少有肉瘤进行全基因组测序，纵向分析或 多区域测序以了解其时空基因组变异性。这种可变性是考虑的 对于理解治疗反应和失败至关重要，并且迫切需要将这些问题联系起来 大多数肿瘤类型中药物敏感性定量方面的分子特征。 我们已经建立了一条管道来开发个性化的骨肉瘤器官来筛选数百种药物 并确定每个肿瘤的耐药性和敏感性。我们将其与全基因组搭配 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到 研究骨肉瘤的分子和药理行为在单个患者中如何在空间上有所不同 （AIM 1）以及它们在过渡到致命转移性疾病的过渡期间的变化（AIM 2）。这 研究将使我们能够定义骨肉瘤转移如何分歧和对治疗的反应并确定 可操作的药物敏感性，并创建详细的肖像，说明骨肉肉瘤如何在治疗下进化 选择性压力，与临床结果有关。