Liquid biopsy approaches to inform osteosarcoma prognosis and tumor evolution

项目摘要/摘要 骨肉瘤是一种侵袭性的骨骼恶性肿瘤，影响儿童和年轻人。海流 骨肉瘤的治疗标准使用了30年来一直使用的相同的化疗方案， 结果没有改变。努力用新的药物和治疗方法改善对这种疾病的治疗 强化在很大程度上是不成功的。造成这种情况的一个潜在原因是缺乏可靠的预测 这种疾病的生物标志物。因此，大多数新的候选治疗方法都是在患有 复发或转移性疾病，不包括新诊断的局部疾病患者，他们可能处于高- 治疗失败的风险。 尽管为了解骨肉瘤的生物学而进行了密集的研究，但大多数研究都是 在诊断时缺乏将复发的基因组特征与临床结果相关联的能力。肿瘤的类型 导致复发的进化仍未得到研究。用于研究的连续肿瘤活检样本是 由于与麻醉和手术相关的安全问题，无法用于进化研究 孩子们。因此，人们对骨肉瘤导致复发的基因组特征知之甚少。 最新可用的液体活组织检查技术能够检测血液中循环肿瘤DNA(CtDNA) 癌症患者。在某些恶性肿瘤中，ctdna水平与预后和ctdna水平的变化有关。 与疾病的反应和进展相对应。在这个项目中，从患者身上收集了大量的血液样本 将用于研究ctDNA水平与新诊断的骨肉瘤预后的相关性 定位骨肉瘤并验证ctDNA作为新的预后生物标志物。 循环肿瘤细胞(CTCs)也可以从骨肉瘤患者的外周血中分离出来，并 当没有肿瘤样本时，提供另一种肿瘤细胞来源以供分析。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。与深沉一起 CtDNA测序，系列样本将用于识别肿瘤异质性的复发模式和 骨肉瘤的疾病演变。这些研究将从根本上拓宽对 骨肉瘤基因组，疾病的自然病史，并验证新的预后生物标记物 在不久的将来改变我们治疗骨肉瘤患者的方式。

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.