Exosomal Thomsen-Friedenreich glycoantigen as a new biomarker for lung cancer screening and early detection

外泌体 Thomsen-Friedenreich 糖抗原作为肺癌筛查和早期检测的新生物标志物

• 批准号: 10670439
• 负责人: GRACE DY
• 金额: $ 21.96万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670439
• 关键词: A549; Affinity; Age; Antibodies; Area Under Curve; Benign; Biological Assay; Biological Markers; Biopsy; Blood; Cancer Diagnostics; Cancer Patient; Carcinoma; Cell surface; Cells; Clinical; Clinical Data; Colon Carcinoma; Companions; Complement; Consumption; Data; Development; Diagnosis; Diagnostic; Disease model; Early Diagnosis; Gender; Guidelines; Histology; IgG3; Immune; Individual; Lung nodule; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Medical Imaging; MicroRNAs; Modeling; Monitor; Monoclonal Antibodies; Mutation; Neoplasm Circulating Cells; Nodule; Non-Small Cell Adenocarcinoma; Non-Small-Cell Lung Carcinoma; Normal Cell; Normal tissue morphology; Patient Monitoring; Patient Selection; Patients; Performance; Portraits; Proteins; Proteome; Radiation exposure; Receiver Operating Characteristics; Reporting; Risk; Role; Sampling; Scanning; Screening for cancer; Sensitivity and Specificity; Serum; Signal Transduction; Smoking History; Specificity; Surface Plasmon Resonance; TNM; Testing; Therapeutic Agents; Time; Tumor-Derived; Validation; Variant; X-Ray Computed Tomography; biobank; biomarker discovery; cancer biomarkers; cancer cell; cancer diagnosis; chest computed tomography; clinical application; cohort; computed tomography screening; cost effective; detection limit; diagnostic accuracy; diagnostic value; exosome; high risk; improved; in-vitro diagnostics; liquid biopsy; low dose computed tomography; lung basal segment; lung cancer cell; lung cancer screening; malignant breast neoplasm; mortality; potential biomarker; screening; small cell lung carcinoma; specific biomarkers; treatment response; tumor; tumor DNA

PROJECT SUMMARY Although lung cancer mortality has improved in recent years, it remains the leading cancer killer worldwide. Low dose computed tomography (CT) scan screening in high-risk patients has shown improved cancer-specific survival, however, it carries >95% of false-positive rate, a subsequent risk of unnecessary invasive diagnostic biopsy, and repeated radiation exposure. Liquid biopsy assays have been developed to overcome these challenges and to enhance the diagnostic accuracy of CT-screened lung nodules. Among many biomarkers, tumor-derived exosomes (TEXs) have emerged as potent cancer biomarkers. We have discovered a new exosomal marker, Thomsen-Friedenreich glycoantigen (TF-Ag-α; Galβ1-3GalNAc alpha), as a potential biomarker for lung cancer early detection. TF-Ag-α is a unique target expressed on the cell surface of about 84% lung cancers (both nonsmall cell and small cell lung cancer) and other carcinomas (such as breast cancer, colon cancer, etc), but not on normal tissues. Currently there are no reports about TEX TF-Ag-α and its roles in the screening and early detection of lung cancer and other cancers. In this project, we select lung cancer as the disease model and aim to demonstrate the clinical utility of TEX TF-Ag-α in cancer liquid biopsy. To transform our discovery to clinical applications, we have developed a monoclonal antibody, JAA-F11, with high specificity to TF-Ag-α and a surface plasmon resonance (SPR)-based liquid biopsy assay to measure the levels of exosomal TF-Ag-α in blood. We have demonstrated, for the first time, that exosomes carry TF-Ag-α. More importantly, we successfully detected exosomal TF-Ag-α in as low as 10uL serum samples from both early stage and late stage nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients, but little signals from those of normal controls. Based on our promising pilot data, we hypothesize that exosomal TF-Ag-α is a potent biomarker for lung cancer screening and early detection. In this project, we propose to (1) further develop the liquid biopsy assay and comprehensively characterize its sensing performances including analytical sensitivity (limit of detection, limit of quantitation), specificity, linear range, and repeatability; (2) demonstrate the diagnostic values of exosomal TF-Ag-α in lung cancer screening and early detection using both cell-derived exosomes and serum samples from well-defined cohorts of patients including lung cancer patients (both NSCLC and SCLC), individuals with benign pulmonary nodules at high risk of lung cancer and normal controls with no pulmonary nodules (total n=200). We aim to develop an effective cancer specific biomarker and an accurate liquid biopsy assay to complement the diagnosis of pulmonary nodules detected during low dose CT screening and to enhance the accuracy of low dose CT.

项目总结 尽管肺癌死亡率近年来有所改善，但它仍然是全球头号癌症杀手。低 高危患者的剂量计算机断层扫描筛查显示癌症特异性有所改善 然而，它的存活率为95%的假阳性，这带来了不必要的侵入性诊断的风险。 活组织检查和反复放射暴露。液体活组织检查已经被开发出来，以克服这些 挑战，并提高CT扫描的肺结节的诊断准确性。在众多生物标志物中， 肿瘤来源的外切体(TES)已成为一种有效的癌症生物标志物。我们发现了一种新的 胞外标记物Thomsen-Friedenreich糖抗原(Tf-Ag-α；Galβ1-3GalNAcα)作为潜在的 肺癌早期发现的生物标志物。Tf-Ag-α是表达于细胞表面约84%的唯一靶点 肺癌(非小细胞肺癌和小细胞肺癌)和其他癌症(如乳腺癌、结肠癌 癌症等)，但不在正常组织上。目前还没有关于Tex Tf-Ag-α及其在血管生成中的作用的报道。 肺癌和其他癌症的筛查和早期发现。在这个项目中，我们选择肺癌作为 目的探讨TeX Tf-Ag-α在癌液活检中的临床应用价值。转型 为了将我们的发现应用于临床，我们研制出了一种具有高度特异性的单抗JAA-F11 以Tf-Ag-α和表面等离子体层析为基础的液体活检法测定 血中胞外体Tf-Ag-α。我们首次证明了外体携带Tf-Ag-α。更多 重要的是，我们成功地在两个早期阶段低至10uL的血清样本中检测到外体Tf-Ag-α 以及晚期非小细胞肺癌(NSCLC)和小细胞肺癌(SCLC)患者，但信号很少 与正常对照组相比。基于我们有希望的实验数据，我们假设外体Tf-Ag-α是一种 肺癌筛查和早期检测的有效生物标志物。在本项目中，我们建议(1)进一步发展 液体活组织检查，并全面表征其检测性能，包括分析 灵敏度(检测限、定量限)、特异度、线性范围和重复性；(2)证明 胞外Tf-Ag-α联合检测在肺癌筛查和早期诊断中的价值 Exosome和来自包括肺癌患者(NSCLC)在内的明确队列患者的血清样本 和小细胞肺癌)，良性肺结节是肺癌的高危个体，正常对照组没有 肺结节(共200个)。我们的目标是开发一种有效的癌症特异性生物标志物和一种准确的 液体活检法对低剂量CT扫描发现的肺结节的辅助诊断 提高低剂量CT扫描的准确性。