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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要在美国，每年约有 16,000 人被诊断患有肉瘤。肉瘤位居第三影响儿童的常见癌症约占所有诊断的儿童肿瘤的 15%。骨肿瘤是其中最为罕见，每年发病人数不到 3,500 例，占所有癌症的 0.2%。尽管积极治疗，总体而言 5 年生存率约为 60%，转移性疾病的 5 年生存率约为 30%。关于一线化疗以外的骨肉瘤药物敏感性的数据有限。与此同时，还有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超出外显子组。至关重要的是，很少有肉瘤进行过全基因组测序、纵向分析或多区域测序以了解其时空基因组变异性。这种变化被认为对于理解治疗反应和失败至关重要，并且仍然迫切需要将这些联系起来大多数肿瘤类型中药物敏感性的分子特征到定量方面。我们已经建立了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概况。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性。在这里我们将利用这个管道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性疾病到致命性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定义骨肉瘤转移如何分化以及对治疗的反应并识别可行的药物敏感性，并详细描述骨肉瘤在治疗下如何演变选择压力，与临床结果相关。