Personalized assessment of bladder cancer treatment response using urinary molecular biomarkers

膀胱癌是美国第六大常见癌症，复发率是所有固体癌症中最高的之一 癌症，是从确诊到死亡治疗费用最高的癌症。退伍军人患癌症的风险增加 由于烟草使用率和环境暴露较高，导致膀胱癌。还有大量未得到满足的需求 用于生物标志物和分子诊断工具，以更好地为膀胱各个阶段的决策提供信息 癌症。对于早期疾病的患者，目前的诊断方法要么是侵入性的(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，这将导致更多 针对局限性膀胱癌患者的有效和个性化的治疗策略。肿瘤来源 尿液等生物体液中的核酸是一种很有前途的非侵入性检测生物标志物。 疾病负担和对治疗的反应。此前，我们开发了膀胱癌生物标记物的流水线。 临床翻译的发现、验证和技术集成。我们应用了高通量的RNA 尿沉渣测序作为生物标志物发现工具并确定尿液信使核糖核酸(u-信使核糖核酸)组 具有前景看好的诊断性能。同时，我们验证了一种集成的微流控墨盒 使用一个单独的u-信使核糖核酸小组，在90分钟内完成“样本输入，答案输出”。我们最近的初步数据 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 优化的mRNA板用于膀胱癌的监测和风险分层；2)验证优化的使用。 用于改进膀胱癌筛查和评估风险分层的mRNA板；以及3)验证优化的 U-mRNA板用于卡介苗治疗高危NMIBC的疗效评估和监测 免疫疗法。我们的团队由经验丰富的退伍军人管理局学术调查人员领导，具有丰富的专业知识 分子诊断学(Liao)、泌尿外科肿瘤学(Liao，Leppert)和临床验证性研究设计(Liao，Yu)。 这里建议的研究的成功完成将成为纳入尿液为基础的基础 生物标志物在膀胱癌监测和前瞻性临床试验中的应用，以评估治疗干预措施。 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。

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.