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

项目 3：应用液体活检技术检测 LMS 治疗的临床反应和耐药机制

• 批准号: 10493631
• 负责人: Brian Crompton
• 金额: $ 51.22万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10493631
• 关键词: Adult; Anesthesia procedures; Biological Markers; Biology; Biopsy; Biopsy Specimen; Blood; Blood specimen; Cancer Biology; Chemoresistance; Chemotherapy-Oncologic Procedure; Clinical; Clinical Research; Clinical Trials; Clonal Evolution; Collection; Consensus; Correlation Studies; Cytotoxic Chemotherapy; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Disease Resistance; Doxorubicin; Enrollment; Evolution; Future; Gene Mutation; Genetic; Genomics; Heterogeneity; Image; In Vitro; Lead; Lesion; Malignant Neoplasms; Metastatic Leiomyosarcoma; Modality; Modeling; Mutation; Newly Diagnosed; Oncologist; Operative Surgical Procedures; Outcome; Patient-Focused Outcomes; Patients; Pattern; Pilot Projects; Plasma; Prognosis; Prognostic Factor; Prognostic Marker; Progression-Free Survivals; Proxy; Radiology Specialty; Recurrence; Regimen; Relapse; Research; Research Personnel; Resistance; Risk; Safety; Sampling; Single Nucleotide Polymorphism; Smooth Muscle; Soft tissue sarcoma; Solid; Systemic Therapy; Technology; Testing; Time; Toxic effect; Treatment Failure; Treatment Futility; Unresectable; Validation; Variant; base; burden of illness; chemotherapy; clinical care; clinical decision-making; cohort; deep sequencing; design; disease natural history; disorder control; docetaxel; experience; experimental study; gemcitabine; genomic profiles; high risk; improved; improved outcome; in vivo; insight; leiomyosarcoma; liquid biopsy; next generation sequencing; novel; novel strategies; novel therapeutic intervention; patient derived xenograft model; patient subsets; personalized medicine; prevent; prognostic; prospective; radiation risk; radiological imaging; resistance mechanism; response; side effect; single cell sequencing; therapy resistant; treatment response; treatment strategy; tumor; tumor DNA; tumor heterogeneity

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.

项目3：项目概要/摘要 平滑肌肉瘤是一种侵袭性软组织肉瘤， 分化，是成人最常见的STS之一。近一半的患者会发生转移性 无论是在诊断之前还是在临床护理期间。化疗是治疗的主要方式 标准化疗方案使用阿霉素或吉西他滨。这些 化疗药物具有显著的毒性风险，但只有15-20%的患者会经历客观的毒性反应。 只有5-10%的人能够长期控制疾病。中位无进展生存期 用阿霉素或基于吉西他滨的方案治疗的转移性LMS患者为6个月。 尽管密集的研究努力，以了解LMS的生物学，大多数研究已经不足， 将诊断时复发的基因组特征与临床结果相关联。肿瘤演变的模式 由于相关的安全性问题，复发和化疗耐药性的增加尚未进行研究 通过麻醉和手术获得一系列肿瘤活检用于研究。新可用液体活检 这些技术能够检测癌症患者血液中的循环肿瘤DNA（ctDNA）。在一些 在恶性肿瘤中，ctDNA水平与预后相关，ctDNA水平的变化对应于疾病 反应和进展。在项目3中，前瞻性收集转移性肝癌患者的血液样本， 接受多柔比星或吉西他滨/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水平和临床结果作为目标1。的数据 生物标志物研究也将验证ctDNA作为新的预后生物标志物。基因拷贝数的改变 目标1中生物标志物研究入组患者的LMS也将作为潜在预后因素进行检查 以及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 可以用作肿瘤活检样品测序的替代物。有证据表明， ctDNA比任何单一活检样品更好地代表转移性疾病患者的基因组异质性。 在目的2中，我们提出对连续ctDNA样品进行分析以鉴定肿瘤异质性的复发模式， LMS中的疾病演变，并验证与化疗相关的获得性遗传变化 使用患者来源的异种移植物模型的耐药性。这些研究将对发展一个 生物标志物的LMS和LMS治疗，并将从根本上拓宽理解LMS和自然 这种疾病的历史。证实产生抗性疾病的进化机制可能会导致 开发新的治疗方法，旨在防止耐药性的出现， 在不久的将来，转移性LMS患者的结局。