PROJECT 3: Applying Liquid Biopsy Technologies to Detect Clinical Response and Mechanisms of Resistance in the Treatment of LMS

项目3：项目摘要/摘要 平滑肌肉瘤(LMS)是一种侵袭性软组织肉瘤(STS)，有平滑肌表现。 分化是成人最常见的性传播疾病之一。近一半的患者会发生转移 在诊断之前或在临床护理期间的疾病。化疗是治疗的主要手段。 转移性LMS，标准化疗方案使用阿霉素或吉西他滨。这些 化疗药物有很大的毒性风险，但只有15%-20%的患者会经历客观的 只有5%-10%的人将实现长期疾病控制。中位无进展生存期 转移性LMS患者接受阿霉素或以吉西他滨为基础的方案治疗6个月。 尽管进行了密集的研究来了解LMS的生物学，但大多数研究都没有足够的能力来 诊断时复发的基因组特征与临床结果相关。肿瘤进化的模式使 由于相关的安全问题，复发和化疗耐药性的上升仍未得到研究 通过麻醉和手术获得连续的肿瘤活检供研究。新推出的液体活检 技术使检测癌症患者血液中的循环肿瘤DNA(CtDNA)成为可能。在一些 恶性肿瘤、ctdna水平与预后相关，ctdna水平的变化与疾病相对应。 反应和进展。在项目3中，对转移性癌症患者的血液样本进行了前瞻性采集 接受阿霉素或吉西他滨/多西他赛化疗的LMS将用于研究 新诊断的转移性LMS患者的ctDNA水平和临床转归作为目标1。 生物标记物研究也将证实ctDNA是一种新的预后生物标记物。基因的拷贝数改变 在AIM 1的生物标志物研究中登记的患者的LMS也将被作为潜在的预后因素进行检查。 以及对一线化疗耐药的生物标志物。最近的研究表明，ctDNA的深度测序 可作为肿瘤活检样本测序的替代方法。有证据表明，来自 在转移性疾病患者中，ctDNA比任何单一的活检样本更能反映基因组的异质性。 在目标2中，我们建议对连续的ctDNA样本进行分析，以确定肿瘤异质性和 LMS的疾病演变，并验证与化疗相关的已识别的获得性基因变化 使用患者来源的异种移植模型的抵抗力。这些研究将对制定一项 LMS和LMS治疗的生物标志物，将从根本上拓宽对LMS和自然 这种疾病的病史。对导致抗药性疾病的进化机制的验证可能导致 开发新的治疗方法，旨在防止耐药性的出现和改善 转移性LMS患者近期的预后。

Project 3: Project Summary / Abstract Leiomyosarcoma (LMS) is an aggressive soft tissue sarcoma (STS) with evidence of smooth muscle differentiation and is one of the most common STS in adults. Nearly half of patients will develop metastatic disease either prior to diagnosis or during their clinical care. Chemotherapy is the primary modality for treatment of metastatic LMS, and the standard chemotherapy regimens use doxorubicin or gemcitabine. These chemotherapy agents carry a significant risk of toxicity, yet only 15-20% of patients will experience an objective response and only 5-10% will achieve long-term disease control. The median progression-free survival for patients with metastatic LMS treated with either doxorubicin or a gemcitabine-based regimen is 6 months. Despite intensive research efforts to understand the biology of LMS, most studies have been underpowered to correlate recurrent genomic features at diagnosis with clinical outcomes. Patterns of tumor evolution that give rise to relapse and chemotherapy resistance have remained unstudied due to the safety concerns associated with anesthesia and surgery to obtain serial tumor biopsies for research. 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 Project 3, a prospective collection of blood samples from patients with metastatic LMS receiving doxorubicin or gemcitabine/docetaxel chemotherapy will be used to study the correlation between ctDNA levels and clinical outcomes in patients with newly diagnosed metastatic LMS as Aim 1. Data from the biomarker study will also validate ctDNA as a novel prognostic biomarker. Copy number alterations of genes in LMS from patients enrolled in the biomarker study in Aim 1 will also be examined as potential prognostic factors and biomarkers of resistance to front-line chemotherapy. Recent studies show that deep sequencing of ctDNA can be used as a proxy for sequencing of tumor biopsy samples. Evidence suggests that genomic profiles from ctDNA better represent genomic heterogeneity in patients with metastatic disease than any single biopsy sample. In Aim 2, we propose to profile serial ctDNA samples to identify recurrent patterns of tumor heterogeneity and disease evolution in LMS, and to validate identified acquired genetic changes associated with chemotherapy resistance using patient-derived xenograft models. These studies will have a major impact on development of a biomarker for LMS and LMS treatment and will fundamentally broaden the understanding of LMS and the natural history of this disease. Validation of mechanisms of evolution that give rise to resistant disease could lead to development of novel therapeutic approaches designed to prevent the emergence of resistance and improve outcomes for patients with metastatic LMS in the near future.