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: 10514572
• 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/10514572
• 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; Clinical; Clinical Trials; Clinical Trials Design; Clinics and Hospitals; 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; 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 Assessment; Risk Factors; Sampling; Scientist; Screening for cancer; Services; Smoke; Smoking; Solid; Staging; Symptoms; Technology; Testing; Therapeutic Intervention; Tobacco use; Translations; Transurethral Resection; Tumor-Derived; Urine; Urologic Diseases; Urologic Oncology; Urologic Surgeon; Validation; Veterans; Vietnam; agent orange; biomarker discovery; biomarker panel; burden of illness; burn pit; cancer risk; cancer type; clinical translation; diagnostic strategy; diagnostic tool; 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癌症，在所有固体中，复发率最高 癌症是从诊断到死亡的最昂贵的癌症。退伍军人的风险增加 由于烟草使用率较高和环境暴露率，膀胱癌。有很大的未满足需求 用于生物标志物和分子诊断工具，以更好地为bladeder的所有阶段的决策提供信息 癌症。对于患有早期疾病的患者，当前的诊断方法要么是侵入性的（例如膀胱镜检查） 或缺乏灵敏度（例如尿细胞学）。我们建议开发分子诊断，这将导致更多 针对局部膀胱癌患者的有效和个性化的治疗策略。肿瘤来源 生物液中的核酸，例如代表非侵入性测量的有望生物标志物的尿液 伯恩疾病和对治疗的反应。以前，我们开发了用于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。我们应用了高吞吐量RNA 尿液沉积物作为生物标志物发现工具的测序，并鉴定出尿mRNA（U-MRNA）面板 具有有希望的诊断性能。同时，我们验证了一个能够集成的微流体墨盒 使用单独的U-MRNA面板在90分钟内“样品中的回答”。我们最近的初步数据 通过将两个面板组合在集成 墨盒。基于这些承诺的初步数据，我们提出了三个具体目标：1）验证 优化了用于膀胱癌监测和风险分层的mRNA面板； 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； 3）验证优化 u-MRNA面板，用于用BCG治疗的高风险NMIBC患者的响应评估和监测 免疫疗法。我们的团队由经验丰富的学术VA调查员领导，具有免费的专业知识 分子诊断（LIAO），泌尿科肿瘤学（LIAO，Leppert）和临床验证研究设计（LIAO，YU）。 成功完成此处提出的研究将成为纳入基于尿液的基础 膀胱癌监测的生物标志物，并进行前瞻性临床试验，以评估治疗性干预措施。 我们预见我们的方法将允许个性化治疗策略来改善卑诗省的结果 退伍军人和普通人群的患者。