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

联系人 PD/PI：曾勇 项目概要 尤文肉瘤 (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。 经过过去几十年的巨大努力，儿科 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，并且对长期生存的改善微乎其微 EWS已经实现。 患者最初 诊断时没有临床明显转移的患者有 5- 年总生存率 相比之下，70-75%； 5年总生存率 转移性 EWS 低于 30%，因为 疾病复发/复发的患病率很高。 对于病情有限的患者，长期生存率为 22% 至 24% 局部复发，远处复发甚至更低 组织活检用于病理或细胞学诊断 EWS 的监测极具侵入性且困难，特别是对于幼儿。 血液生物标志物对 EWS 的治疗和管理提出了严重障碍，更重要的是， 因此，迫切需要新的诊断和预后生物标志物来检测复发性或转移性 EWS。 改善这种致命的儿科癌症的临床结果正在成为一种新的循环外泌体。 用于非侵入性癌症诊断和监测的“液体活检”范例是小膜。 大多数细胞分泌的大小为 30-150 nm 的囊泡，越来越多的证据表明其具有重要的生物学作用。 外泌体的临床相关性在多种癌症中，已发现肿瘤来源的外泌体。 在人类生物体液（例如血液）中积累，并富含一组来自细胞的生物分子 然而，生物学和临床上，蛋白质和RNA等可能构成“癌症特征”。 外泌体的价值在很大程度上仍然未知，部分原因是分离和分析此类外泌体的挑战 EWS 中的外泌体研究很少（如果有的话）。 据报道，为了解决 EWS 分析技术和精准医学方面的明显差距。 建议开发和验证受纳米技术启发的集成微流体平台，该平台提供 用于测量循环外泌体中蛋白质和 mRNA 标记物的前所未有的分析能力 这些新技术将被验证以分析独特的循环外泌体。 儿科 EWS 患者在初次诊断、治疗期间和结束后的纵向系列血液样本 疗法，旨在识别可以跟踪治疗反应并检测早期疾病的外泌体标记物 虽然该项目专门针对 EWS 作为原理验证而设计，但最终将提供重复性。 用于多种恶性肿瘤基础和临床研究的变革性平台技术 疾病。 。 项目总结/摘要第 7 页