Identification of serum protein biomarkers by profiling N-glycoproteomes of patient-derived xenografts of neuroendocrine prostate cancer

通过分析神经内分泌前列腺癌患者来源的异种移植物的 N-糖蛋白质组来鉴定血清蛋白生物标志物

• 批准号: 10572514
• 负责人: JAMES D. BROOKS
• 金额: $ 21.8万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572514
• 关键词: Adenocarcinoma; Benign Prostatic Hypertrophy; Bioinformatics; Biological Assay; Biological Markers; Biopsy; Cancer Histology; Cancer Patient; Castration; Cell surface; Clinic; Clinical; Clinical Trials; Cryopreservation; Cryopreserved Tissue; Databases; Development; Disease; Extracellular Matrix; Foundations; Fractionation; Future; Glycopeptides; Glycoproteins; Goals; Histologic; Human; Image; Immunodeficient Mouse; International; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Mass Spectrum Analysis; Measurement; Measures; Methods; Monitor; Monitoring for Recurrence; Mus; Neuroendocrine Prostate Cancer; Non-Invasive Detection; Pathologic; Patient Monitoring; Patient Selection; Patient Triage; Patients; Peptides; Pharmaceutical Preparations; Procedures; Prostate Adenocarcinoma; Protein Glycosylation; Protein Isoforms; Proteins; Proteomics; Quality of life; Reaction; Resistance; Resolution; Resources; Sampling; Sensitivity and Specificity; Series; Serum; Serum Proteins; Systemic Therapy; Testing; Time; Tumor Subtype; Tumor Tissue; Tumor Volume; Validation; Variant; androgen deprivation therapy; biomarker discovery; cancer biomarkers; candidate marker; candidate selection; candidate validation; chemotherapy; cohort; glycoproteomics; glycosylation; implantation; improved; individualized medicine; mass spectrometer; novel; novel strategies; novel therapeutics; patient derived xenograft model; patient response; potential biomarker; profiles in patients; programs; protein biomarkers; protein complex; resistance mechanism; response; specific biomarkers; standard of care; targeted treatment; therapy development; treatment response; tumor; tumor xenograft

PROJECT SUMMARY Neuroendocrine prostate cancer (NEPC) is a lethal variant of prostate cancer (PCa) that may arise de novo or in 17-30% of patients previously treated with standard of care androgen deprivation therapy (ADT) for prostate adenocarcinoma (AC) as a mechanism of resistance. Serum biomarkers with high sensitivity and specificity for non-invasive detection for NEPC are urgently needed to enable clinicians to select the proper next-line systemic therapy in a timely manner, select of patients for clinical trials, and monitor treatment responses that entail reversing the NEPC state. A novel strategy that allows quick identification of ‘‘human- unique’’ proteins in a mouse serum background, thereby overcoming limitations associated with proteomics- based biomarker discovery, has been used successfully to identify serum glycoprotein biomarkers in ovarian cancer patient-derived xenografts (PDX). We hypothesize that PCa PDX tumors that reflect human PCa express unique tumor-associated glycoproteins that can be readily identified in sera of tumor-bearing mice using mass spectrometry. Moreover, different serum glycoproteins and their levels are associated with different subtypes of PCa PDXs, namely, pure AC, AC mixed with NEPC, and pure NEPC. Finally, these subtype specific biomarkers can be used to identify NEPC in clinical samples from PCa patients. In Aim 1, we will identify novel serum glycoproteins associated with subtypes of PCa PDX tumors by glycoproteomic analyses of PDX sera. Specifically, PDX tumors will be generated using cryopreserved tissues from publically available PDXs lines with pure AC, AC mixed with NEPC and pure NEPC histology by subrenal implantation into immunodeficient mice. Quantitative proteomics will be performed to generate glycoproteomic profiles of PDX sera and human-specific proteins will be selected bioinformatically. In Aim 2, serum proteins found in samples with a NEPC component but not expressed in pure AC samples will be selected. The top 5 candidate NEPC-specific biomarkers for which a targeted assay is developed successfully will be validated in sera from PDX mice and patients with pathologically confirmed NEPC component. The sensitivity and specificity of these biomarkers will be assessed using sera from patients with pathologically confirmed AC and benign prostatic hyperplasia as true negative control. Our approach would lead to biomarkers that could be developed quickly for use in the clinic to reduce morbid biopsies and appropriately triage patients to therapies tailored to their disease state, which in turn, will improve quality of life and survival. In addition, these biomarkers could be used to monitor patient response to standard-of-care therapies and select patients for clinical trials testing novel therapies developed in the future that target NEPC specifically. Moreover, the subtype-specific glycoproteins we identified could serve as the basis for future imaging strategies or targeted therapies. Finally, the glycoproteomes of NEPC will provide a valuable resource for better understanding the mechanisms of NEPC development.

项目摘要 神经内分泌前列腺癌（NEPC）是可能出现的前列腺癌（PCA）的致命变体 NOVO或17-30％的先前接受过护理标准雄激素剥夺治疗（ADT）治疗的患者 前列腺腺癌（AC）作为抗药性机制。具有高灵敏度的血清生物标志物 迫切需要针对NEPC的非侵入性检测的特异性，以使临床医生能够选择适当的 及时及时选择临床试验的患者，并监测治疗 需要逆转NEPC状态的响应。一种新颖的策略，可以快速识别“人类” 在小鼠血清背景下的独特'’蛋白质，从而克服了与蛋白质组学相关的限制 - 基于生物标志物的发现已成功地用于识别卵巢中的血清糖蛋白生物标志物 癌症患者衍生的Xenographictic（PDX）。我们假设反映人PCA的PCA PDX肿瘤 在肿瘤小鼠血清中很容易鉴定出与独特的肿瘤相关糖蛋白 使用质谱法。此外，不同的血清糖蛋白及其水平与不同 PCA PDX的亚型，即纯AC，AC与NEPC和纯NEPC混合。最后，这些亚型 特定的生物标志物可用于鉴定来自PCA患者的临床样本中的NEPC。 在AIM 1中，我们将确定与PCA PDX肿瘤亚型相关的新型血清糖蛋白 PDX血清的糖蛋白质组学分析。具体而言，将使用冷冻保存组织生成PDX肿瘤 从纯AC，AC与NEPC和纯NEPC组织学混合的公开可用的PDXS线。 植入免疫缺陷小鼠。将进行定量蛋白质组学以产生糖蛋白质组学 PDX血清和人类特异性蛋白的曲线将是生物信息的。在AIM 2中，血清蛋白 将选择在具有NEPC分量但未在纯AC样品中表达的样品中发现的。前五名 成功开发有针对性测定的候选NEPC特异性生物标志物将在 来自PDX小鼠的血清和具有病理确认的NEPC成分的患者。灵敏度和 这些生物标志物的特异性将使用病理确认的AC和AC患者的血清评估 良性前列腺增生为真正的阴性对照。 我们的方法将导致生物标志物可以迅速开发用于诊所以减少 病态的活检和适当的分类患者，以适合其疾病状态的疗法，这反过来将 提高生活质量和生存。此外，这些生物标志物可用于监视患者对 护理标准疗法和选择的患者用于临床试验，对未来开发的新疗法进行了新的疗法 该针对NEPC。此外，我们确定的亚型特异性糖蛋白可以用作 未来成像策略或有针对性疗法的基础。最后，NEPC的糖蛋白酶将提供 有价值的资源，以更好地了解NEPC开发的机制。