Lung Cancer Early Detection and Immunotherapy Response Prediction and Monitoring with an Exo-PROS Liquid Biopsy Assay

使用 Exo-PROS 液体活检测定进行肺癌早期检测和免疫治疗反应预测和监测

基本信息

批准号：
10665754
负责人：
GRACE DY
金额：
$ 63.02万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10665754
关键词：
Address Antigens Area Under Curve Biological Assay Biological Markers Biopsy Biosensing Techniques Biosensor Blood Body Fluids Cancer Etiology Cancer Patient Carbohydrates Cell Communication Cell secretion Cells Cessation of life Clinical Complement Consumption Data Development Diagnostic Diagnostic Sensitivity Diagnostic tests Disease Early Diagnosis Early treatment Enzyme-Linked Immunosorbent Assay Epidermal Growth Factor Receptor Image Immune checkpoint inhibitor Immunotherapy In Situ Malignant Neoplasms Malignant neoplasm of lung Measurement Medical Imaging Methods MicroRNAs Minority Monitor Non-Small-Cell Lung Carcinoma Normal Cell Patient Care Patient Selection Patient-Focused Outcomes Patients Performance Pilot Projects Portraits Prediction of Response to Therapy Predictive Value Procedures Proteins Quantitative Reverse Transcriptase PCR RNA Radiation exposure Risk Factors Sampling Sensitivity and Specificity Serum Specificity Survival Rate Technology Testing Time Tissues Tumor Markers Tumor-Derived anti-PD1 therapy cancer biomarkers checkpoint therapy clinical decision-making cohort cost effective diagnostic accuracy diagnostic value effective therapy exosome extracellular vesicles high risk imaging modality improved liquid biopsy low dose computed tomography lung cancer screening mortality nanosized overexpression pembrolizumab predicting response predictive marker programmed cell death ligand 1 recruit responders and non-responders response screening screening guidelines sensor small cell lung carcinoma standard of care user-friendly

项目摘要

PROJECT SUMMARY Lung cancer causes about 25% of all cancer deaths worldwide. Early detection and effective treatment are critical in reducing the mortality. Low-dose computed tomography (CT) is the recommended screening test for lung cancer, however, its high false-positive rate leads to unnecessary biopsy and repeated radiation exposure. Immune checkpoint inhibitors (ICIs) have revolutionized treatment for lung cancer, however, they are only effective for a minority of patients. Predicting and monitoring responses to ICIs by tissue biopsy and imaging are limited by invasive procedure, the lack of effective tumor biomarkers, pseudo progression, and delayed response. Therefore, non-invasive, accurate and affordable methods are urgently needed to detect lung cancer early and to effectively predict and monitor response to ICIs, aiding in improving patient outcomes. Liquid biopsy detects tumor-derived biomarkers in body fluids such as blood, complements imaging and risk factor data, allows sequential monitoring of cancer development, and thus represents a new and non-invasive strategy to address these unmet needs. Exosomes are nano-sized extracellular vesicles secreted by cells. They are actively involved in every step of cancer development and have emerged as promising cancer biomarkers. We hypothesize that tumor-derived exosomes (TEXs) are highly sensitive and specific for lung cancer early detection and treatment response prediction and monitoring, and the combination of TEX markers provides superior diagnostic and predictive performances than single markers alone. A major challenge in developing exosomes-based cancer biomarkers is the separation of TEXs from exosomes released by normal cells, the latter of which can render the test less sensitive or incapable of detecting TEX biomarkers. To overcome this challenge, we have developed an exosome protein RNA one stop (Exo-PROS) biosensor. The Exo-PROS assay first selectively captures TEXs from non-TEXs using cancer- overexpressed markers, and then, for the first time, provides one-stop and in-situ quantitation of three types of TEX biomarkers including proteins, microRNAs and carbohydrate antigens. In our pilot study, we demonstrated that combined TEX biomarkers (EGFR, miR-21, LG3BP, miR-210, TF-Ag-α) distinguished lung cancer from normal controls with sensitivity of 1.00 and specificity of 1.00. We also showed that TEX PD-L1, miR-21 and TF-Ag-α successfully predicted the response to anti-PD-1 therapy in lung cancer patients. In this project, we will (1) further develop the Exo-PROS assay and characterize its analytical performances including sensitivity, specificity, linear range and repeatability; (2) determine the diagnostic values of Exo-PROS assay in lung cancer early detection and demonstrate that Exo-PROS assay complements low dose CT and improves the diagnostic accuracy; (3) evaluate Exo-PROS assay in predicting and monitoring response to anti-PD-1 therapy, and demonstrate that Exo-PROS assay is an effective test to complement tissue biopsy and imaging modalities in clinical decision making and patient care.

项目概要肺癌导致全球约 25% 的癌症死亡，需要早期发现和有效治疗。低剂量计算机断层扫描 (CT) 是降低死亡率的关键。然而，肺癌假阳性率较高，导致不必要的活检和重复放疗免疫检查点抑制剂 (ICIs) 彻底改变了肺癌的治疗方法，但它们仍然存在。仅对少数患者通过组织活检和监测对 ICI 的反应有效。成像受到侵入性操作、缺乏有效的肿瘤生物标志物、假性进展和因此，迫切需要非侵入性、准确且经济的方法来检测。早期有效地预测和监测肺癌对 ICI 的反应，有助于改善患者的预后。液体活检可检测血液等体液中肿瘤衍生的生物标志物，补充成像和风险因素数据，允许对癌症发展进行连续监测，因此代表了一种新的非侵入性方法解决这些未满足需求的策略外泌体是细胞分泌的纳米大小的细胞外囊泡。他们积极参与癌症发展的每一步，并已成为有前途的癌症我们认为肿瘤来源的外泌体（TEX）对肺具有高度敏感性和特异性。癌症早期检测和治疗反应预测和监测，以及TEX标记的组合与单独的单一标记物相比，提供了卓越的诊断和预测性能。开发基于外泌体的癌症生物标志物的一个主要挑战是将 TEX 与正常细胞释放的外泌体，后者会使测试不太敏感或无法进行为了克服这一挑战，我们开发了一种外泌体蛋白 RNA 一站式检测。 (Exo-PROS) 生物传感器 Exo-PROS 检测首先使用 cancer- 从非 TEX 中选择性捕获 TEX。过表达的标记物，然后首次提供三种类型的一站式和原位定量在我们的初步研究中，我们展示了 TEX 生物标志物，包括蛋白质、microRNA 和碳水化合物抗原。结合 TEX 生物标志物（EGFR、miR-21、LG3BP、miR-210、TF-Ag-α）将肺癌与正常对照的敏感性为 1.00，特异性为 1.00。我们还表明，TEX PD-L1、miR-21 和 TF-Ag-α 成功预测了肺癌患者对抗 PD-1 治疗的反应。将 (1) 进一步开发 Exo-PROS 测定并表征其分析性能，包括灵敏度、 (2)确定Exo-PROS测定在肺部的诊断价值癌症早期检测并证明 Exo-PROS 检测可补充低剂量 CT 并改善诊断准确性；(3) 评估 Exo-PROS 检测在预测和监测抗 PD-1 反应中的作用疗法，并证明 Exo-PROS 测定是补充组织活检和成像的有效测试临床决策和患者护理的方式。