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.

筛查前列腺癌可以挽救生命，但会导致绝大多数男性受到 不必要的侵入性前列腺活检，以及过度诊断和治疗惰性癌症的风险。多- 前列腺的参数MRI（mpMRI）和分子生物标志物用于评估临床上 显著的前列腺癌（csPCa）和需要活检，但是它们在检测的准确性方面是有限的。 csPCa，导致许多男性仍然需要进行活检，因为担心错过重要的肿瘤。这项建议 解决了提高csPCa检测精度以减少前列腺负担的重要问题 癌症筛查由癌细胞释放到体液中的细胞外囊泡（EV）是有希望的 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 反映了母体肿瘤。问题是选择性地提取从前列腺癌释放的电动汽车， 具有挑战性，并且非前列腺来源的EV的贡献可以降低检测和特异性。合作 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，我们已经开发了一种方法来富集表达前列腺特异性 膜抗原（PSMA）表面蛋白。我们已经发现，PSMA EV捕获富集导致 检测EV mRNA和长链非编码RNA的不同且可能更具有前列腺特异性的谱。 然而，虽然EV内容物被脂质膜很好地保护，但收集和 表达PSMA表面蛋白的EV的加工尚未严格定义。在我们提出的 项目，我们将专注于开发一种对csPCa更具特异性的尿PSMA EV检测方法， 目前可用于PCa的测试。具体而言，我们将检验通过PSMA获得的尿液EV 富集可以提供一组EV RNA标记物，其可以显著增加前列腺癌风险 考核在具体目标1中，我们制定了一项创新的多因素检测开发计划， 以前在表面抗原捕获的严格性和再现性方面的限制，并开发最佳工作流程 用于PSMA富集。在具体目标2中，我们将对富集的PSMA进行RNAseq综合分析。 正在进行的U迈阿密（MDSelect：NCT 04240327）临床试验中招募了250例患者， 进行活检以评价csPCa，以确定PSMA富集相对于总EV的附加值 用于csPCa检测。在具体目标3中，我们将开发和验证一种新的尿EV特征，以增强 使用来自PSMA富集和总EV的RNAseq数据进行csPCa检测的准确性， 在正在进行的NCI EDRN（NCT 03784924）临床试验中进行验证。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 生物标志物测定显著增强了csPCa检测，并在临床试验中得到验证。这项建议会 显著增强csPCa检测，并为未来基于EV的前列腺癌标志物奠定基础。