The Rigor and Clinical Utility of PSMA Enriched Extracellular Vesicles for Prostate Cancer Detection

富含 PSMA 的细胞外囊泡用于前列腺癌检测的严谨性和临床实用性

• 批准号: 10745084
• 负责人: SANDRA M GASTON
• 金额: $ 52.03万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-12 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10745084
• 关键词: Address; Aliquot; Antigens; Biological Assay; Biological Markers; Biopsy; Biopsy Specimen; Blood; Body Fluids; Cancer Patient; Cessation of life; Clinical; Clinical Trials; Collaborations; Collection; Data; Detection; Development; Development Plans; Diagnosis; Diagnostic; Diagnostic tests; Early Detection Research Network; Enrollment; Epitopes; Evaluation; FOLH1 gene; Foundations; Fright; Future; Genes; Goals; Indolent; Institution; Liquid substance; Localized Malignant Neoplasm; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Membrane Lipids; Membrane Proteins; Messenger RNA; Methods; Molecular; Oncogenes; Outcome; Parents; Patients; Positioning Attribute; Preparation; Prostate; Protocols documentation; RNA; RNA Sequences; RNA marker; Reproducibility; Research; Research Design; Risk; Risk Assessment; Risk Reduction; Sampling; Screening for Prostate Cancer; Series; Source; Specificity; Standardization; Structure of base of prostate; Surface Antigens; Testing; Tissues; Training; Transcript; Tumor Tissue; Untranslated RNA; Urine; Validation; artificial intelligence algorithm; assay development; biomarker discovery; cancer biomarkers; cancer cell; cancer risk; clinical risk; clinical trial enrollment; clinically relevant; clinically significant; cohort; detection limit; differential expression; exosome; experimental study; extracellular vesicles; genetic signature; improved; innovation; liquid biopsy; men; molecular marker; novel; participant enrollment; prediction algorithm; prostate biopsy; prostate cancer risk; pyrrolidin-3-yl-methanesulfonic acid; research and development; research clinical testing; screening; standard of care; transcriptome sequencing; tumor; urinary; vesicular release

Screening for prostate cancer saves lives but results in an overwhelming number of men being subjected to unnecessary, invasive prostate biopsies, and the risk of over diagnosis and treatment of indolent cancer. Multi- parametric MRI (mpMRI) of the prostate and molecular biomarkers are used to evaluate the risk of clinically significant prostate cancer (csPCa) and need for biopsy, however they are limited in their accuracy for detecting csPCa, resulting in many men still needing to undergo biopsy for fear of missing a significant tumor. This proposal addresses an important issue in enhancing the precision of csPCa detection to reduce the burdens of prostate cancer screening. Extracellular Vesicles (EVs) that are released into body fluids by cancer cells are promising biomarkers for liquid biopsy since they can be extracted from blood and urine and carry molecular constituents reflecting the parent tumor. The problem is selectively extracting EVs released from prostate cancers can be challenging, and contribution by EVs of non-prostate origin can lessen detection and specificity. In collaboration with the research and development team at Exosome Diagnostics, who are experts in the field of clinical-grade EV biomarker analysis, we have developed a method to enrich for EVs expressing the Prostate Specific Membrane Antigen (PSMA) surface protein. We have found that PSMA EV capture enrichment results in the detection of a different, and potentially more prostate specific profile of EV mRNAs and long non-coding RNAs. However while EV contents are well protected by lipid membranes, optimal conditions for the collection and processing of EVs expressing PSMA surface protein have not yet been rigorously defined. In our proposed project, we will focus on development of a urine PSMA EV assay that is more specific for csPCa than the other currently available tests for PCa. Specifically, we will test the hypothesis that the urine EVs obtained by PSMA enrichment can provide a panel of EV RNA markers that can substantially enhance prostate cancer risk assessment. In Specific Aim 1, we have developed an innovative multi-factor assay development plan to address previous limitations in the rigor and reproducibility of surface antigen capture and develop an optimal workflow for PSMA enrichment. In Specific Aim 2, we will conduct RNAseq comprehensive profiling of PSMA enriched and total EVs from men in an ongoing U Miami (MDSelect: NCT04240327) clinical trial enrolling 250 patients undergoing biopsy for evaluation of csPCa to determine the additive value of PSMA enrichment over total EVs for csPCa detection. In Specific Aim 3, we will develop and validate a novel urinary EV signature to enhance the accuracy of csPCa detection using RNAseq data from PSMA enriched and total EVs, with multi-institutional validation in an ongoing NCI EDRN (NCT03784924) clinical trial. Based on our preliminary data and the combined expertise of our research team we are well positioned to develop and deliver an EV based urine biomarker assay that significantly enhances csPCa detection with validation in clinical trials. This proposal will substantially enhance csPCa detection and lay the foundation for future EV based prostate cancer markers.

前列腺癌筛查可以挽救生命，但导致绝大多数男性罹患前列腺癌 不必要的侵入性前列腺活检，以及惰性癌症过度诊断和治疗的风险。多- 前列腺参数 MRI (mpMRI) 和分子生物标志物用于评估临床风险 严重的前列腺癌 (csPCa) 并需要活检，但检测的准确性有限 csPCa，导致许多男性仍然需要接受活检，因为担心遗漏重要的肿瘤。这个提议 解决了提高 csPCa 检测精度以减轻前列腺负担的重要问题 癌症筛查。癌细胞释放到体液中的细胞外囊泡（EV）前景广阔 用于液体活检的生物标志物，因为它们可以从血液和尿液中提取并携带分子成分 反映母体肿瘤。问题是选择性地提取前列腺癌释放的 EV 具有挑战性，并且非前列腺来源的 EV 的贡献可能会减少检测和特异性。合作中 与 Exosome Diagnostics 的研发团队合作，他们是临床级领域的专家 EV 生物标志物分析，我们开发了一种方法来丰富表达前列腺特异性的 EV 膜抗原 (PSMA) 表面蛋白。我们发现 PSMA EV 捕获富集结果 检测不同的、可能更具前列腺特异性的 EV mRNA 和长非编码 RNA。 然而，虽然 EV 内容物受到脂膜的良好保护，但收集和使用的最佳条件 表达 PSMA 表面蛋白的 EV 的加工尚未得到严格定义。在我们提出的 项目中，我们将重点开发一种尿液 PSMA EV 检测方法，该检测方法比其他方法对 csPCa 更具特异性 目前可用于 PCa 的测试。具体来说，我们将检验以下假设：PSMA 获得的尿液 EV 富集可提供一组 EV RNA 标记物，可显着提高前列腺癌风险 评估。在具体目标 1 中，我们制定了一项创新的多因素检测开发计划来解决 先前在表面抗原捕获的严格性和再现性方面的限制并开发最佳的工作流程 用于 PSMA 富集。在具体目标 2 中，我们将对富含 PSMA 的 RNAseq 进行全面分析 迈阿密大学正在进行的一项招募 250 名患者的临床试验（MDSelect：NCT04240327）中男性的 EV 和总 EV 进行活检以评估 csPCa，以确定 PSMA 富集相对于总 EV 的附加价值 用于 csPCa 检测。在具体目标 3 中，我们将开发并验证一种新型尿液 EV 特征，以增强 多机构使用来自 PSMA 富集和总 EV 的 RNAseq 数据进行 csPCa 检测的准确性 正在进行的 NCI EDRN (NCT03784924) 临床试验中进行了验证。根据我们的初步数据和 结合我们研究团队的专业知识，我们有能力开发和提供基于 EV 的尿液 生物标志物测定可显着增强 csPCa 检测并在临床试验中进行验证。该提案将 显着增强 csPCa 检测，并为未来基于 EV 的前列腺癌标记物奠定基础。