Integrated exosomes profiling for minimally invasive diagnosis and monitoring of cancer

联系PD/PI：曾勇 项目总结 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。Desp 经过几十年的努力，儿科EWS的早期发现仍然是 对标准成像和细胞遗传学模式的挑战，以及对长期生存的极小改善 已经实现了EWS。 最初的病人 在诊断时没有临床表现的转移瘤有5- 年总存活率 70%-75%；相比之下， 5年总生存期 转移性EWS低于30%的原因是 疾病复发/复发的高发生率。 长期存活率为22%至24%的患者 局部复发，远端复发组织活检病理或细胞学诊断更低 而且对EWS的监测是极其侵入性和困难的，特别是在幼儿中。缺乏可靠的 血液生物标志物是EWS治疗和管理的严重障碍，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来 改善这种致命的儿科癌症的临床结果。循环外切体正在成为一种新的 用于非侵入性癌症诊断和监测的“液体活检”范例。外切小体是小的膜 大多数细胞分泌30-150 nm大小的小泡。越来越多的证据显示了重要的生物学作用 和外切体的临床相关性。在各种癌症中，已发现肿瘤来源的外切体是 积聚在人体生物体液中，如血液，并富含一组来自人的细胞的生物分子 来源，如蛋白质和RNA，这可能构成“癌症的标志”。然而，生物学和临床 外切体的价值仍然在很大程度上是未知的，部分原因是在分离和分析这些外切体方面存在挑战 小的、动态的和分子多样性的囊泡。EWS中的exosome研究很少，如果有的话 据报道。为了解决EWS在分析技术和精确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，该平台可提供 前所未有的分析能力来测量循环外切体中的蛋白质和信使核糖核酸标记 派生自EWS。这些新技术将得到验证，可以在一种独特的 儿科EWS患者初诊、治疗期间和停药时的血样纵向序列 治疗，旨在识别能够跟踪治疗反应和发现早期疾病的胞外标志物 复发。虽然该项目旨在专门针对EWS作为原则证明，但最终将提供 变革性平台技术，用于广泛的恶性肿瘤和临床研究 疾病。 。 项目摘要/摘要第7页

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