Analysis of urine tumor nucleic acids for detection and personalized surveillance of bladder cancer

尿液肿瘤核酸分析用于膀胱癌的检测和个性化监测

• 批准号: 10656481
• 负责人: Ash Arash Alizadeh
• 金额: $ 58.51万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656481
• 关键词: Address; Adjuvant Chemotherapy; Aftercare; BCG Live; Bacillus Calmette-Guerin Therapy; Biological; Biological Assay; Biological Markers; Blood; Cancer Detection; Cancer Diagnostics; Cancer Patient; Cancer Personalized Profiling by Deep Sequencing; Cells; Cessation of life; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Cystectomy; Cystoscopy; Cytology; DNA; DNA Methylation; DNA Sequence Alteration; DNA analysis; Data; Decision Making; Detection; Detection of Minimal Residual Disease; Development; Diagnosis; Diagnostic; Diagnostic Sensitivity; Disease; Distant; Doctor of Philosophy; Early Diagnosis; Early identification; Foundations; Goals; Hematuria; High-Throughput Nucleotide Sequencing; In complete remission; Liquid substance; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measurement; Medical Oncologist; Methods; Methylation; Molecular; Monitor; Neoadjuvant Therapy; Nucleic Acids; Oncologist; Pathologic; Patients; Performance; Physicians; Prediction of Response to Therapy; RNA; RNA methylation; Radiation Oncologist; Radical Cystectomy; Recurrence; Research; Research Design; Research Personnel; Residual state; Risk; Scientist; Sensitivity and Specificity; Solid; Source; Specificity; Testing; Transurethral Resection; Tumor-Derived; Urine; Urogenital Cancer; Urologic Surgeon; Work; biomarker panel; burden of illness; cancer type; cohort; design; detection method; diagnostic strategy; diagnostic tool; experience; high risk; improved; improved outcome; intravesical; molecular diagnostics; molecular marker; muscle invasive bladder cancer; mutant; non-muscle invasive bladder cancer; novel; novel marker; novel strategies; nucleic acid detection; patient stratification; personalized approach; personalized medicine; personalized therapeutic; prospective; response; risk prediction; risk stratification; screening; side effect; treatment response; treatment strategy; trial design; tumor; tumor DNA; urinary; urologic

PROJECT SUMMARY Bladder cancer (BC) 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. There are significant unmet needs for biomarkers and molecular diagnostic tools to better inform decision making across all stages of BC. This includes prediction of treatment response in patients with non-muscle invasive (NMIBC) and muscle invasive bladder cancer (MIBC), as well as improving diagnostic yield in patients undergoing screening cystoscopy for hematuria. Our long-term goal is to improve outcomes for BC patients through the development and application of molecular biomarkers that facilitate personalized approaches to detection and treatment. Urine is an attractive source for development of BC diagnostics and we recently developed a novel strategy for detecting urine tumor DNA called urine tumor DNA Cancer Personalized Profiling by Deep Sequencing (uCAPP-Seq). Our preliminary data indicate that uCAPP-Seq has outstanding sensitivity and specificity for detection and surveillance of BC. In this project we will prospectively collect urine and other biospecimens from patients with or at risk for BC and will test the potential clinical utility of uCAPP-Seq in different clinical scenarios. We will also test if augmenting uCAPP-Seq with analysis of urinary RNA or DNA methylation further augments performance. Our central hypothesis is that uCAPP-Seq will enable monitoring of BC responses during and after treatment for NMIBC and MIBC. Furthermore, we hypothesize that combining analysis of urine DNA mutations, DNA methylation, and urine RNA will allow ultrasensitive and specific early detection of BC. We propose three specific aims: 1) To assess the value of urine tumor DNA for non-invasive response assessment and monitoring in patients with high risk NMIBC treated with bacillus Calmette-Guérin (BCG) immunotherapy; 2) To determine if urine tumor DNA analysis can predict pathologic complete responses to neoadjuvant chemotherapy in patients with MIBC; and 3) To develop a Bladder Cancer Interception Assay (BCIA) which integrates utDNA mutations and methylation with urinary RNA for ultra-sensitive detection of bladder cancer. Successful completion of the studies proposed here will serve as a foundation for incorporating our novel urine-based biomarkers into prospective clinical trials. We foresee that our approach will allow personalization of treatment strategies to improve outcomes for BC patients. Importnatly, our work will serve as proof-of- principle for an approach that could also be applied to other genitourinary cancer types.

项目摘要 膀胱癌（BC）是美国第六大常见癌症，复发率最高的癌症之一 所有的实体癌，是从诊断到死亡治疗费用最高的癌症。存在显著 对生物标志物和分子诊断工具的未满足需求，以更好地为所有阶段的决策提供信息 BC的。这包括预测非肌肉侵入性（NMIBC）患者的治疗反应， 肌肉浸润性膀胱癌（MIBC），以及提高接受筛查的患者的诊断率 膀胱镜检查血尿。我们的长期目标是通过以下方式改善BC患者的结局： 开发和应用分子生物标志物，促进个性化的方法， 检测和治疗。 尿液是开发BC诊断的有吸引力的来源，我们最近开发了一种新的策略， 检测尿液肿瘤DNA称为尿液肿瘤DNA癌症通过深度测序进行个性化分析 （uCAPP-Seq）。我们的初步数据表明，uCAPP-Seq对以下疾病具有突出的灵敏度和特异性： 检测和监测BC。在这个项目中，我们将前瞻性地收集尿液和其他生物标本， 在患有BC或处于BC风险中的患者中，并将在不同的临床试验中测试uCAPP-Seq的潜在临床效用。 场景我们还将测试是否通过分析尿RNA或DNA甲基化进一步增强uCAPP-Seq 增强性能。我们的中心假设是，uCAPP-Seq将能够监测BC NMIBC和MIBC治疗期间和治疗后的反应。此外，我们假设， 结合尿液DNA突变、DNA甲基化和尿液RNA的分析， 和BC的特异性早期检测。我们提出三个具体目标：1）评估尿液肿瘤的价值 DNA用于接受以下治疗的高危NMIBC患者的非侵入性反应评估和监测 卡介苗（BCG）免疫治疗; 2）确定尿液肿瘤DNA分析是否可以预测 MIBC患者对新辅助化疗的病理学完全反应;和3）开发一种 膀胱癌拦截试验（BCIA），其整合了utDNA突变和甲基化， RNA用于膀胱癌的超灵敏检测。 成功完成这里提出的研究将作为一个基础，纳入我们的小说 尿基生物标志物进入前瞻性临床试验。我们预见我们的方法将允许个性化 治疗策略，以改善BC患者的结果。重要的是，我们的工作将作为证据- 这一原则也适用于其他泌尿生殖系统癌症类型。