EFIRM Liquid Biopsy Research Laboratory: Early Lung Cancer Assessment

EFIRM 液体活检研究实验室：早期肺癌评估

• 批准号: 10763321
• 负责人: DENISE R. ABERLE
• 金额: $ 93.21万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-13 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10763321
• 关键词: Address; Algorithms; Benign; Biological Assay; Biological Markers; Blood; Blood Volume; Blood specimen; Cancer Biology; Cancer Detection; Cancer Patient; Characteristics; Classification; Clinical; Collaborations; DNA Sequence Alteration; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Diameter; Diffusion; Disease; Early Diagnosis; Engineering; Ensure; Heterogeneity; Human; Image; Individual; Industry; Laboratories; Laboratory Research; Lesion; Liquid substance; Lung; Lung nodule; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Methods; Methylation; MicroRNAs; Modeling; Molecular; Nodule; Non-Malignant; Non-Small-Cell Lung Carcinoma; Pathologic; Patients; Performance; Phase; Plasma; Population; Predictive Cancer Model; Procedures; Prospective cohort; Qualifying; Recommendation; Research; Resolution; Scanning; Secure; Signal Transduction; Somatic Mutation; Symptoms; Techniques; Technology; Testing; Thoracic Radiography; Tissue Sample; Tumor Markers; Validation; X-Ray Computed Tomography; cancer biomarkers; cancer diagnosis; candidate marker; cell free DNA; chest computed tomography; circulating DNA; cohort; computed tomography screening; curative treatments; deep learning; electric field; former smoker; frontier; histological specimens; improved; industry partner; interest; liquid biopsy; low dose computed tomography; lung cancer screening; malignant state; mortality; multiple omics; never smoker; novel; point of care; pre-clinical; prediction algorithm; predictive modeling; prospective; radiomics; reconstruction; screening; serial imaging; surveillance imaging; tumor DNA

Project Summary/Abstract: Computed tomography (CT) is currently the most sensitive test for detecting preclinical lung cancer. The National Lung Screening Trial (NLST) demonstrated that routine low-dose CT screening reduces lung cancer mortality by 20% relative to chest radiography. However, the increased use of CT has also resulted in the discovery of an estimated 2 million screened and incidentally detected indeterminate pulmonary nodules (IPNs). These nodules, less than 30 mm in diameter, are largely benign but a proportion possess malignancy potential. Methods are urgently needed to better differentiate between individuals with benign disease and those should undergo invasive diagnostic testing. Liquid biopsy has found its way into the cancer lexicon as a reference to tumor biomarkers within blood or other readily accessible biospecimens that reflect the presence and biology of cancer. To fully mature liquid biopsy at the forefront of early cancer assessment, two frontiers must be addressed. The first is the development (discovery and validation) of comprehensive personalized cancer-specific omics targets for early detection. The second is the advancement and refinement of technologies that can detect the earliest shedding of these circulating targets. This application is Phase 2 of the EFIRM-Liquid Biopsy Research Laboratory (E-LBRL) aims to advance these two essential frontiers for early cancer assessment of indeterminate pulmonary nodules (IPNs): early detection of lung cancer. Our partnership interweaves the expertise of lung cancer biologists, clinicians, and biostatisticians with industry engineers, converging on the novel liquid biopsy technology “EFIRM-Liquid biopsy (eLB)”. Complementary to the performance of eLB, during the Phase 1 of E-LBRL, we have discovered a novel species of cell-free DNA which are ultrashort and single-stranded (uscfDNA) and contribute to a population of a large pool of Broad Range cfDNA (BRcfDNA). Unlike circulating tumor DNA which are rare or absent in early states, the uscfDNA represent global/systemic changes in cancer and can be harnessed to detect the malignancy status of the IPN. Additionally, due to their physical characteristics, these BRcfDNA biomarkers are optimal for the eLB platform. We hypothesize that signals from malignancy associated BRcfDNAs can be integrated with malignancy associated somatic mutations, differentiated methylated regions, miRNA and radiomic imaging in an integrated model termed IPN.CA to permit the earliest cancer assessment of IPN. Our industry partner together with a Biomarker Reference Lab will convert individual eLB assays to multiplex arrays for CLIA-qualification. The eLB- IPN.CA and its associated inputs will be a clinically deployable Laboratory Developed Test (LDT) for early cancer assessment in IPN.

项目摘要/摘要： 计算机断层扫描 (CT) 是目前检测临床前肺癌最敏感的测试。 国家肺部筛查试验 (NLST) 表明，常规低剂量 CT 可以减少肺癌筛查 与胸部 X 线检查相比，死亡率降低了 20% 然而，CT 使用的增加也导致了死亡率的增加。 发现了估计 200 万个筛查和偶然发现的不确定性肺结节 (IPN)。 这些直径小于 30 毫米的结节大部分是良性的，但也有一部分具有恶性潜力。 迫切需要方法来更好地区分患有良性疾病的个体和那些应该患有良性疾病的个体。 接受侵入性诊断测试。 液体活检已进入癌症词典，作为血液或血液中肿瘤生物标志物的参考。 其他易于获取的生物样本，反映癌症的存在和生物学特性 至完全成熟的液体。 活检处于早期癌症评估的前沿，必须解决两个前沿问题：第一是发展。 （发现和验证）用于早期检测的全面个性化癌症特异性组学目标。 其次是技术的进步和完善，可以检测到这些物质最早脱落的情况。 该应用是 EFIRM 液体活检研究实验室 (E-LBRL) 目标的第二阶段。 推进不确定性肺结节 (IPN) 早期癌症评估的两个重要前沿： 早期发现肺癌。 我们的合作伙伴关系将肺癌生物学家、资助者和生物统计学家的专业知识与 行业工程师齐聚一堂，研究新型液体活检技术“EFIRM-液体活检（eLB）”。 作为对 eLB 性能的补充，在 E-LBRL 的第一阶段，我们发现了一个新物种 超短单链无细胞 DNA (uscfDNA)，对大量群体有贡献 与早期状态下罕见或不存在的循环肿瘤 DNA 不同， uscfDNA 代表癌症的全球/系统性变化，可用于检测恶性肿瘤 此外，由于其物理特性，这些 BRcfDNA 生物标志物是最佳选择。 eLB平台。 我们追求来自与 BRcfDNA 相关的恶性肿瘤的信号可以与恶性肿瘤整合 相关体细胞突变、分化甲基化区域、miRNA 和放射组学成像 名为 IPN.CA 的模型可与我们的行业合作伙伴一起对 IPN 进行最早的癌症评估。 生物标志物参考实验室将单独的 eLB 检测转换为多重阵列以获得 CLIA 资格。 IPN.CA 及其相关输入将成为临床可部署的早期癌症实验室开发测试 (LDT) IPN 中的评估。