Ultra-short circulating tumor DNA (uctDNA) for liquid biopsy of non-small cell lung cancer

用于非小细胞肺癌液体活检的超短循环肿瘤DNA（uctDNA）

基本信息

批准号：
9916728
负责人：
Feng Li
金额：
$ 20.36万
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：
2019
资助国家：
美国
起止时间：
2019-04-16 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9916728
关键词：
Biologic Characteristic Biological Biological Assay Biopsy Blood Blood Circulation Blood specimen Body Fluids Cancer Detection Cancer Patient Cells Characteristics Clinic Clinical Coupling DNA DNA Library DNA sequencing Data Detection Detection of Minimal Residual Disease Diagnosis Diagnostic tests Drug resistance EGFR gene Enrollment Epidermal Growth Factor Receptor Exons Exploratory/Developmental Grant FDA approved Generations Genomics Genotype Length Libraries Light Los Angeles Lung diseases Medical center Methodology Methods Molecular Profiling Monitor Mutate Mutation Mutation Detection Non-Small-Cell Lung Carcinoma Patient Selection Patients Performance Plasma Procedures Public Health Recovery Reporting Saliva Sampling Single-Stranded DNA Solid Neoplasm Techniques Technology Testing Tissues Tyrosine Kinase Inhibitor Uncertainty Validation Work actionable mutation base cancer diagnosis cancer therapy cell free DNA clinical application cohort digital direct application ds-DNA improved liquid biopsy mutant new technology next generation sequencing novel recruit targeted treatment treatment response tumor tumor DNA

项目摘要

Project Summary/Abstract: Liquid biopsy (LB) is the analysis of cell-free circulating tumor DNA (ctDNA) in readily-accessible body fluids to non-invasively profile the molecular landscape of solid tumors. Liquid biopsy based on ctDNA can be used to detect actionable mutations, monitor response to treatments and assess the emergence of drug resistance. Liquid biopsy is particularly attractive in non-small cell lung cancer (NSCLC) as activating mutations in Epidermal Growth Factor Receptor (EGFR) confer sensitivity to Tyrosine Kinase Inhibitors(1). However, the analytical sensitivity for liquid biopsy technologies for detecting ctDNA and associated genomic changes is limited by its low concentration compared to cell-free DNA (cfDNA) of non-tumor origin. In 2016, FDA approved the Cobas EGFR Mutation Test v2 using plasma as the first liquid biopsy test for diagnostic use. However, the reported sensitivity for the detection of the 2 most common activating mutations (exon 19 deletions or exon 21 substitutions) in the EGFR gene is only 76.7%(2). Improving the sensitivity of mutation detection could further unlock the potential of liquid biopsies for the diagnosis of cancer including earlier stage detection as well as detection of minimal residual disease. Liquid biopsy analytical platforms that deliver detection sensitivity closest to tissue biopsy-based genotyping of tumor-specific ctDNA is an unmet clinical need. Our preliminary study showed the existence of a novel group of ultrashort circulating tumor DNA (uctDNA) molecules with EGFR mutations in plasma samples from non-small cell lung cancer (NSCLC) patients. This NCI Clinical and Translational Exploratory/Developmental Studies R21 application is to explore and test our hypothesis that there are abundant uctDNA molecules in blood and saliva samples from NSCLC and these uctDNA fragments are additional circulating tumor targets that will improve the sensitivity of liquid biopsy. Two specific aims are in place for hypothesis testing. Aim 1 is to recruit, enroll 250 NSCLC patients that from UCLA Medical Center (UCLAMC) Pulmonary Disease Clinic and VA Greater Los Angeles (VA GLA) Pulmonary Disease Clinic. Plasma will be collected from each patient. Aim 2 is to validate clinical utility of uctDNA NGS assay targeting uctDNA for liquid biopsy of NSCLC. Together, the translational and clinical validations, targeting uctDNA for liquid biopsy can break new ground and extend previous discoveries towards impactful new directions and clinical applications.

项目摘要/摘要：液体活检 (LB) 是对易于接近的体内的无细胞循环肿瘤 DNA (ctDNA) 进行分析流体以非侵入性方式描绘实体瘤的分子景观。基于 ctDNA 的液体活检可用于检测可操作的突变、监测治疗反应并评估药物的出现反抗。液体活检在非小细胞肺癌 (NSCLC) 中特别有吸引力，因为它可以激活突变表皮生长因子受体 (EGFR) 中的 EGFR 赋予对酪氨酸激酶抑制剂的敏感性 (1)。然而，用于检测 ctDNA 和相关基因组变化的液体活检技术的分析灵敏度为与非肿瘤来源的游离 DNA (cfDNA) 相比，其浓度较低，因此受到限制。 2016年，FDA批准 Cobas EGFR 突变测试 v2 使用血浆作为第一个用于诊断用途的液体活检测试。然而，报告了检测 2 种最常见激活突变（外显子 19 缺失或外显子 21 EGFR 基因中的替换）仅为 76.7%（2）。提高突变检测的灵敏度可以进一步释放液体活检在癌症诊断方面的潜力，包括早期检测以及微小残留病的检测。提供检测灵敏度的液体活检分析平台最接近基于组织活检的肿瘤特异性 ctDNA 基因分型是一个未满足的临床需求。我们的初步研究表明存在一组新型超短循环肿瘤DNA 非小细胞肺癌 (NSCLC) 血浆样本中具有 EGFR 突变的 (uctDNA) 分子患者。此 NCI 临床和转化探索/发展研究 R21 应用程序旨在探索并检验我们的假设，即 NSCLC 的血液和唾液样本中存在丰富的 uctDNA 分子这些uctDNA片段是额外的循环肿瘤靶标，将提高液体的敏感性活检。假设检验有两个具体目标。目标 1 是招募 250 名 NSCLC 患者来自加州大学洛杉矶分校医学中心 (UCLAMC) 肺部疾病诊所和 VA 大洛杉矶 (VA GLA) 肺部疾病诊所。将从每位患者身上收集血浆。目标 2 是验证临床效用 uctDNA NGS 检测针对 uctDNA，用于 NSCLC 液体活检。结合翻译和临床验证，针对 uctDNA 进行液体活检可以带来新的突破基础并将先前的发现扩展到有影响力的新方向和临床应用。