High-throughput palmitoyl-proteomics profiling of extracellular vesicles for identification of biomarkers for early detection of clinically significant prostate cancer

细胞外囊泡的高通量棕榈酰蛋白质组学分析，用于鉴定生物标志物，从而早期检测有临床意义的前列腺癌

• 批准号: 9753183
• 负责人: Dolores Di Vizio
• 金额: $ 50.7万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753183
• 关键词: Address; Area; Benchmarking; Benign; Biological Markers; Biology; Biopsy; Blood Circulation; Cancer Detection; Cancer Patient; Cancer Prognosis; Categories; Cause of Death; Clinic; Clinical; Clinical assessments; Collaborations; Detection; Development; Diagnosis; Diagnostic; Differential Diagnosis; Disease; Early Diagnosis; Early identification; Evaluation; Flow Cytometry; Future; Goals; Human; Indolent; Institution; LNCaP; Label; Liquid substance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Methodology; Methods; Microfluidic Analytical Techniques; Molecular; Nature; Normal tissue morphology; North America; Patients; Performance; Plasma; Play; Population; Proteins; Proteomics; Publishing; Reproducibility; Reproducibility of Results; Research; Resources; Risk; Role; Screening for Prostate Cancer; Sensitivity and Specificity; Site; Source; Specimen; Standardization; Technology; Translations; Tumor-Derived; Validation; Yang; biomarker development; biomarker discovery; biomarker identification; biomarker panel; cancer cell; cancer type; candidate marker; clinical implementation; clinical predictors; clinically significant; cohort; diagnostic biomarker; differential expression; disorder risk; early detection biomarkers; exosome; extracellular vesicles; high risk; improved; men; multidisciplinary; multiple reaction monitoring; neoplastic cell; next generation; oncology; outcome forecast; overtreatment; palmitoylation; prevent; prognostic; prognostic value; prostate biopsy; prostate cancer cell; prostate cancer cell line; prostate surgery; protein biomarkers; reproductive; research clinical testing; specific biomarkers; standard of care; tumor; tumor microenvironment; tumor progression

This proposal leverages trans-institutional collaboration and multidisciplinary expertise in extracellular vesicle (EV) biology, together with established clinical expertise in oncology, to identify EV-associated biomarkers for the detection, diagnosis and prognosis of early prostate cancer (PC). EVs shed by the tumor and its microenvironment are a very promising source of biomarkers, with the potential to assist with the detection, diagnosis and prognosis of cancer in the clinical setting. This is particularly true for PC where there is an immediate need for improved diagnostics to reduce unnecessary biopsies and over-diagnosis of indolent disease, and for a methodology that will allow thousands of under-diagnosed men who have clinically significant PC to receive appropriate early diagnosis. Unfortunately, the rigor and reproducibility of detecting EV-associated biomarkers with appropriate specificity and sensitivity, as well as a detection approach that provides reproducible results across all clinical settings in North America, have not been achieved. Our recent studies on large oncosomes (LO), which are atypically large EVs (1-10 m), have identified a previously unexplored pool of EV-associated biomarkers that we find predictive of clinically significant PC. As a team with cross-cutting expertise in EV biology, PC, and biomarker discovery, we are collaborating to pursue EV-associated biomarkers that can detect PC with sufficient sensitivity and specificity to diagnose PC early and to distinguish between indolent disease and lethal disease. Our preliminary studies reveal that tumor- derived EVs are readily detected in PC patients. Moreover, an assessment of known markers demonstrates enormous potential for EV-associated biomarkers in the differential diagnosis of early PC. We hypothesize that incorporating robust EV-associated markers into the existing standard of care for PC can reduce cancer- related deaths caused by lethal PC and avoid the overtreatment of indolent disease by improving early detection and differential diagnosis of these patient categories. This multidisciplinary team will address this hypothesis through three Specific Aims: 1) To refine methods leading to reproducible analysis of LO from plasma and serum. 2) Discovery of candidate (palmitoyl)protein biomarkers from purified LO for early identification of clinically significant PC and 3) Clinical testing to assess the diagnostic and prognostic value of LO in early prostate cancer. The project incorporates several next generation technologies and resources to identify cancer-specific biomarkers in circulating LO and assess their performance in independent clinical cohorts of PC patients from the collaborating institutions. Our objective is to implement and validate a rigorous and reproducible methodology for EV analysis with high clinical value.

该提案利用了细胞外囊泡方面的跨机构合作和多学科专业知识 (EV) 生物学，结合肿瘤学方面已建立的临床专业知识，确定与 EV 相关的生物标志物 肿瘤及其脱落的早期前列腺癌 (PC) 的检测、诊断和预后。 微环境是非常有前途的生物标志物来源，有可能协助检测， 临床环境中癌症的诊断和预后对于 PC 来说尤其如此。 迫切需要改进诊断方法，以减少不必要的活检和惰性的过度诊断 疾病，以及一种方法，可以让数千名临床上诊断不足的男性 不幸的是，检测的严谨性和可重复性对 PC 的接受至关重要。 具有适当特异性和敏感性的 EV 相关生物标志物，以及检测方法 我们最近尚未在北美所有临床环境中提供可重复的结果。 对大肿瘤 (LO) 的研究，大肿瘤是非典型的大 EV (1-10 µm)，已经确定了先前的 我们发现未探索的 EV 相关生物标志物可预测具有临床意义的 PC。 作为一支在 EV 生物学、PC 和生物标志物发现方面拥有跨领域专业知识的团队，我们正在合作 寻找能够检测 PC 的 EV 相关生物标志物，并具有足够的敏感性和特异性来诊断 PC 我们的初步研究表明，早期并区分惰性疾病和致命疾病。 此外，对已知标记物的评估表明，派生的 EV 在 PC 患者中很容易检测到。 EV 相关生物标志物在早期 PC 的鉴别诊断中具有巨大潜力。 将强大的 EV 相关标记物纳入现有的 PC 护理标准中可以减少癌症 - 致命PC引起的相关死亡，并通过早期改善避免惰性疾病的过度治疗 这些患者类别的检测和鉴别诊断。 这个多学科团队将通过三个具体目标来解决这一假设：1）完善方法 导致对血浆和血清中的 LO 进行可重复的分析 2) 候选（棕榈酰）蛋白的发现。 来自纯化 LO 的生物标志物，用于早期识别具有临床意义的 PC，以及 3) 临床测试以评估 LO 在早期前列腺癌中的诊断和预后价值 该项目包含以下几个内容。 生成技术和资源来识别循环 LO 中的癌症特异性生物标志物并评估其 我们的目标是评估来自合作机构的 PC 患者的独立临床队列的表现。 实施和验证具有高临床价值的严格且可重复的 EV 分析方法。