Liquid biopsy approaches to inform osteosarcoma prognosis and tumor evolution

液体活检方法可告知骨肉瘤预后和肿瘤演变

• 批准号: 10426209
• 负责人: Brian Crompton
• 金额: $ 40.49万
• 依托单位: DANA-FARBER CANCER INST
• 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/10426209
• 关键词: Address; Adult; Anesthesia procedures; Biological Assay; Biology; Biopsy; Biopsy Specimen; Blood; Blood specimen; Cancer Patient; Cells; Child; Childhood; Clinical; Collection; Complex; Correlation Studies; Detection; Development; Diagnosis; Disease; Disease Surveillance; Event; Evolution; Future; Genome; Genomic Instability; Genomics; Goals; Hematopoietic Neoplasms; Heterogeneity; Individual; Localized Disease; Malignant Neoplasms; Measurement; Neoplasm Circulating Cells; Newly Diagnosed; Operative Surgical Procedures; Outcome; Patients; Pattern; Plasma; Population; Prognosis; Prognostic Marker; Prospective cohort; Recurrence; Recurrent disease; Relapse; Research; Resistance; Retrospective cohort; Risk; Safety; Sampling; Solid; Source; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Treatment Failure; Variant; base; biomarker development; bone; burden of illness; cell free DNA; chemotherapy; cohort; deep sequencing; disease natural history; genome sequencing; high risk; improved; individualized medicine; liquid biopsy; mortality; neoplastic cell; next generation sequencing; novel; novel marker; osteosarcoma; peripheral blood; personalized medicine; prevent; prognostic; response; risk stratification; single cell sequencing; standard care; surveillance strategy; therapy resistant; tissue biomarkers; treatment strategy; tumor; tumor DNA; tumor heterogeneity; whole genome; young adult

PROJECT SUMMARY/ABSTRACT Osteosarcoma is an aggressive malignancy of the bone that effects children and young adults. The current treatment standard for osteosarcoma utilizes the same chemotherapy that has been used for 30 years and outcomes have remained unchanged. Efforts to improve therapy for this disease with novel agents and treatment intensification have been largely unsuccessful. One potential reason for this is the lack of reliable prognostic biomarkers for this disease. As a result, most new candidate treatment approaches are tested in patients with relapsed or metastatic disease, excluding patients with newly diagnosed localized disease who may be at high- risk of treatment failure. Despite intensive research efforts to understand the biology of osteosarcoma, most studies have been underpowered to correlate recurrent genomic features at diagnosis with clinical outcomes. Patterns of tumor evolution that give rise to relapse have remained unstudied. Serial tumor biopsy samples for research are unavailable for evolutionary studies due to the safety concerns associated with anesthesia and surgery in children. Therefore, little is known about the genomic features of osteosarcoma that give rise to relapse. Newly available liquid biopsy technologies enable the detection of circulating tumor DNA (ctDNA) in the blood of patients with cancer. In some malignancies, ctDNA levels correlate with prognosis and changes in ctDNA levels correspond to disease response and progression. In this project, a large collection of blood samples from patients with osteosarcoma will be used to study the correlation between ctDNA levels and outcomes in newly diagnosed localized osteosarcoma and validate ctDNA as a new prognostic biomarker. Circulating tumor cells (CTCs) can also be isolated from the peripheral blood of patients with osteosarcoma and provides an alternative source of tumor cells for profiling when tumor samples are not available. In this study, CTCs from patients with osteosarcoma will be captured for single-cell profiling of tumor cells. Together with deep sequencing of ctDNA, serial samples will be used to identify recurrent patterns of tumor heterogeneity and disease evolution in osteosarcoma. These studies will fundamentally broaden the understanding of the osteosarcoma genome, the natural history of the disease, and validate novel biomarkers of outcome that could alter the way we treat patients with osteosarcoma in the near future.

项目概要/摘要 骨肉瘤是一种侵袭性骨骼恶性肿瘤，影响儿童和年轻人。目前的 骨肉瘤的治疗标准采用与30年来相同的化疗方法 结果保持不变。努力通过新的药物和治疗方法改善这种疾病的治疗 强化行动基本上没有成功。造成这种情况的一个潜在原因是缺乏可靠的预后 这种疾病的生物标志物。因此，大多数新的候选治疗方法都在患有以下疾病的患者中进行了测试 复发或转移性疾病，不包括新诊断的局部疾病可能处于高位的患者 治疗失败的风险。 尽管为了解骨肉瘤的生物学进行了深入的研究工作，但大多数研究都是 无法将诊断时反复出现的基因组特征与临床结果关联起来。肿瘤的形态 引起复发的进化仍未得到研究。用于研究的系列肿瘤活检样本是 由于与麻醉和手术相关的安全问题，无法进行进化研究 孩子们。因此，对于导致复发的骨肉瘤的基因组特征知之甚少。 新推出的液体活检技术能够检测血液中的循环肿瘤 DNA (ctDNA) 癌症患者。在某些恶性肿瘤中，ctDNA 水平与预后和 ctDNA 水平的变化相关 与疾病反应和进展相对应。在这个项目中，收集了大量患者的血液样本 骨肉瘤将用于研究新诊断的 ctDNA 水平与结果之间的相关性 局限性骨肉瘤并验证 ctDNA 作为新的预后生物标志物。 循环肿瘤细胞（CTC）也可以从骨肉瘤患者的外周血中分离出来， 当无法获得肿瘤样本时，提供了用于分析的肿瘤细胞的替代来源。在这项研究中， 来自骨肉瘤患者的 CTC 将被捕获，用于肿瘤细胞的单细胞分析。与深一起 ctDNA 测序，系列样本将用于识别肿瘤异质性的重复模式 骨肉瘤的疾病演变。这些研究将从根本上拓宽人们对 骨肉瘤基因组、疾病的自然史，并验证新的结果生物标志物 在不久的将来改变我们治疗骨肉瘤患者的方式。