Personalized assessment of bladder cancer treatment response using urinary molecular biomarkers

使用尿液分子生物标志物对膀胱癌治疗反应进行个性化评估

• 批准号: 10015540
• 负责人: JOSEPH C LIAO
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10015540
• 关键词: Adult; Afghanistan; Aromatic Amines; Awareness; BCG Live; Bacillus Calmette-Guerin Therapy; Benign; Biological; Biological Markers; Bladder; Blood; Cancer Detection; Cancer Patient; Cessation of life; Chemical Exposure; Clinic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Collaborations; Cystoscopy; Cytology; Data; Decision Making; Development; Diagnosis; Diagnostic; Diagnostic Sensitivity; Disease; Doctor of Philosophy; Emotional; Environmental Exposure; Epidemiologist; Exposure to; Foundations; General Population; Goals; Health; Health Services Accessibility; Hematuria; High-Throughput RNA Sequencing; Hospitals; Iraq; Lesion; Liquid substance; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measurement; Measures; Medical; Messenger RNA; Microfluidics; Microscopic; Modeling; Molecular; Monitor; Morbidity - disease rate; Nucleic Acids; Operative Surgical Procedures; Particulate; Patients; Performance; Population; Prediction of Response to Therapy; Procedures; Recording of previous events; Recurrence; Research; Research Design; Research Personnel; Residual Cancers; Risk; Risk Factors; Sampling; Scientist; Screening for cancer; Services; Smoke; Smoking; Solid; Symptoms; Technology; Testing; Therapeutic Intervention; Time; Tobacco use; Translations; Transurethral Resection; Tumor-Derived; Urine; Urologic Diseases; Urologic Oncology; Urologic Surgeon; Validation; Veterans; Vietnam; agent orange; base; biomarker discovery; biomarker panel; burden of illness; cancer risk; cancer type; clinical translation; experience; falls; high risk; improved; improved outcome; intravesical; molecular diagnostics; molecular marker; non-muscle invasive bladder cancer; patient stratification; personalized approach; personalized medicine; personalized therapeutic; prospective; response; risk stratification; screening; tool; treatment response; treatment strategy; tumor; urinary; validation studies

Bladder cancer is the sixth most common cancer in the U.S., has one of the highest recurrence rates of all solid cancers, and is the most expensive cancer to treat from diagnosis to death. Veterans are at increased risk for bladder cancer due higher rates of tobacco use and environmental exposure. There are significant unmet needs for biomarkers and molecular diagnostic tools to better inform decision making across all stages of bladder cancer. For patients with early stage disease, current diagnostic approaches are either invasive (e.g. cystoscopy) or lack sensitivity (e.g. urine cytology). We propose to develop molecular diagnostics that will lead to more effective and personalized therapeutic strategies for patients with localized bladder cancer. Tumor-derived nucleic acids in biological fluids such as urine represent promising biomarkers for non-invasive measurement of disease burden and response to therapy. Previously, we developed a pipeline for bladder cancer biomarker discovery, validation, and technology integration for clinical translation. We applied high throughput RNA sequencing of urinary sediments as a biomarker discovery tool and identified a urinary mRNA (u-mRNA) panel with promising diagnostic performance. In parallel, we validated an integrated microfluidics cartridge capable of “sample-in, answer-out” within 90 minutes using a separate u-mRNA panel. Our recent preliminary data indicate further improvement of diagnostic performance by combining the two panels within the integrated cartridge. Based on these promising preliminary data, we propose three specific aims: 1) to validate the optimized mRNA panel for bladder cancer surveillance and risk stratification; 2) to validate the optimized u- mRNA panel to improve bladder cancer screening and assess risk stratification; and 3) to validate the optimized u-mRNA panel for response assessment and monitoring in patients with high risk NMIBC treated with BCG immunotherapy. Our team is led by experienced academic VA investigators with complimentary expertise in molecular diagnostics (Liao), urologic oncology (Liao, Leppert), and clinical validation study design (Liao, Yu). Successful completion of the studies proposed here will serve as a foundation for incorporating urine-based biomarkers in bladder cancer surveillance and into prospective clinical trials to assess therapeutic interventions. We foresee that our approach will allow personalization of treatment strategies to improve outcomes for BC patients in both veterans and the general population.

膀胱癌是美国第六大常见癌症，是所有固体中复发率最高的之一 是从诊断到死亡治疗费用最高的癌症。退伍军人面临的风险增加 膀胱癌是由于烟草使用率和环境暴露率较高。存在大量未满足的需求 生物标志物和分子诊断工具，以更好地为膀胱所有阶段的决策提供信息 癌对于早期疾病患者，目前的诊断方法是侵入性的（例如膀胱镜检查） 或缺乏敏感性（例如尿细胞学）。我们建议发展分子诊断学， 为局限性膀胱癌患者提供有效和个性化的治疗策略。肿瘤来源 生物流体如尿中的核酸代表了用于非侵入性测量的有希望的生物标志物， 疾病负担和对治疗的反应。以前，我们开发了一种膀胱癌生物标志物的管道， 临床翻译的发现、验证和技术集成。我们将高通量RNA 尿沉积物测序作为生物标志物发现工具，并确定了尿mRNA（u-mRNA）面板 具有良好的诊断性能。同时，我们验证了一种集成的微流体盒， 在90分钟内使用单独的u-mRNA面板进行“样本输入，答案输出”。我们最近的初步数据 表明通过将两个面板组合在集成的 弹药筒基于这些有希望的初步数据，我们提出了三个具体目标：1）验证 用于膀胱癌监测和风险分层的优化mRNA组; 2）验证优化的u- mRNA面板，以改善膀胱癌筛查和评估风险分层;以及3）验证优化的 用于BCG治疗的高危NMIBC患者的反应评估和监测的u-mRNA组 免疫疗法。我们的团队由经验丰富的学术VA调查人员领导，他们具有以下方面的专业知识： 分子诊断学（Liao）、泌尿肿瘤学（Liao，Leppert）和临床验证研究设计（Liao，Yu）。 成功完成这里提出的研究将作为一个基础， 膀胱癌监测和前瞻性临床试验中的生物标志物，以评估治疗干预。 我们预见，我们的方法将允许个性化的治疗策略，以改善BC的结果 退伍军人和普通人群中的患者。