Integrated exosomes profiling for minimally invasive diagnosis and monitoring of cancer

用于癌症微创诊断和监测的综合外泌体分析

• 批准号: 10307656
• 负责人: ANDREW K. GODWIN
• 金额: $ 19.59万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307656
• 关键词: Integrated; exosomes; profiling; minimally; invasive

Contact PD/PI: Zeng, Yong PROJECT SUMMARY Ewing Sarcoma (EWS) is the second most common primary bone cancer and a deadly threat to US children and adolescents. Desp ite great efforts over the last few decades, early detection of pediatric EWS is still challenging for standard imaging and cytogenetic modalities and very little improvement in long-term survival of EWS has been achieved. Patients initially presenting without clinically overt metastases at diagnosis have a 5- year overall survival of 70-75%; in contrast, the 5-year overall survival for metastatic EWS is below 30% due to high prevalence of disease recurrence/relapse. The long-term survival is 22% to 24% for patients with limited localized relapse and even lower for distant relapse Tissue biopsy for pathological or cytological diagnosis and monitoring of EWS is extremely invasive and difficult, especially in young children. The lack of reliable blood biomarkers presents a serious obstacle to the treatment and management of EWS, more importantly, recurrent or metastatic EWS. Thus novel diagnostic and prognostic biomarkers are urgently needed to improve clinical outcome of this deadly pediatric cancer. Circulating exosomes are emerging as a new paradigm of “liquid biopsy” for non-invasive cancer diagnosis and monitoring. Exosomes are small membrane vesicles of 30-150 nm in size secreted by most cells. Growing evidence has shown important biological roles and clinical relevance of exosomes. In various cancers, tumor-derived exosomes have been found to be accumulated in human biofluids, such as blood, and enriched with a set of biomolecules from the cells of origin, such as proteins and RNAs, which may constitute a “cancer signature”. However, biology and clinical value of exosomes remain largely unknown, due in part to the challenges in isolation and analysis of such small, dynamic and molecularly diverse vesicles. Very few, if any, exosome studies in EWS have been reported. To address this obvious gap in both analytical technologies and the precision medicine for EWS, we propose to develop and validate the nanotechnology-inspired, integrated microfluidic platforms that offer unprecedented analytical capabilities for measuring protein and mRNA markers in circulating exosomes derived from EWS. These new technologies will be validated to profile circulating exosomes in a unique longitudinal series of blood samples from pediatric EWS patients at initial diagnosis, during therapy and off therapy, aiming to identify exosomal markers that can track therapeutic response and detect early disease recurrence. While designed to specifically target EWS as proof-of-principle, this project will ultimately provide transformative platform technologies for basic and clinical investigation of a wide range of malignancies and diseases. . Project Summary/Abstract Page 7

联系PD/PI：Zeng，Yong 项目摘要 尤因肉瘤（EWS）是第二常见的原发性骨癌，对美国儿童构成致命威胁 和青少年。Desp 尽管在过去几十年中付出了巨大的努力，但儿童EWS的早期发现仍然是一个难题。 对标准成像和细胞遗传学模式具有挑战性， EWS已经实现。 患者最初 在诊断时没有临床明显转移的患者有5- 年总生存 70-75%;相比之下， 5-年总生存 对于转移性EWS低于30%， 疾病复发/再发率高。 长期生存率为22%至24%， 局部复发，远处复发更低组织活检病理或细胞学诊断 EWS的监测是非常侵入性和困难的，特别是在幼儿中。缺乏可靠的 血液生物标志物对EWS的治疗和管理构成严重障碍，更重要的是， 复发或转移性EWS。因此，迫切需要新的诊断和预后生物标志物， 改善这种致命儿科癌症的临床结果。循环外泌体正在成为一种新的 这是一种用于非侵入性癌症诊断和监测的“液体活检”范例。外泌体是一种小膜 大多数细胞分泌的30-150 nm大小的囊泡。越来越多的证据表明， 和临床相关性。在各种癌症中，已经发现肿瘤来源的外泌体是肿瘤细胞的主要来源。 在人类生物流体中积累，如血液，并富含一组来自细胞的生物分子， 癌症起源，如蛋白质和RNA，可能构成“癌症特征”。然而，生物学和临床 外来体的价值在很大程度上仍然未知，部分原因是分离和分析这种外来体的挑战。 小的、动态的和分子多样的囊泡。很少有，如果有的话，EWS中的外泌体研究已经 报道为了解决EWS分析技术和精准医学方面的这一明显差距，我们 建议开发和验证受纳米技术启发的集成微流体平台， 前所未有的分析能力，用于测量循环外泌体中的蛋白质和mRNA标记物 源自EWS。这些新技术将被验证，以独特的方式分析循环外泌体。 来自儿科EWS患者在初始诊断时、治疗期间和停药时的血液样本的纵向系列 治疗，旨在确定可以跟踪治疗反应和检测早期疾病的外泌体标记物 复发虽然专门针对EWS作为原理验证而设计，但该项目最终将提供 用于广泛恶性肿瘤基础和临床研究的变革性平台技术， 疾病 . 项目摘要/摘要第7页