Blood-based monitoring of bladder-sparing trimodality therapy for muscle-invasive bladder cancer

保留膀胱三联疗法治疗肌层浸润性膀胱癌的血液监测

• 批准号: 10366341
• 负责人: David T. Miyamoto
• 金额: $ 59.71万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366341
• 关键词: Biological Assay; Bladder; Bladder Neoplasm; Blood; Cancer Biology; Cancer Patient; Cancer Survivor; Cellular Assay; Clinical; Clinical Trials; Consensus; Cystectomy; Cystoscopy; Data; Development; Disease; Early Diagnosis; Enrollment; Evolution; Expression Profiling; Gene Expression Profile; Genetic Transcription; Goals; Guidelines; Image; Immune; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Methodology; Methods; Microfluidics; Molecular; Molecular Profiling; Monitor; Monitoring for Recurrence; Neoplasm Circulating Cells; Outcome; Patient Monitoring; Patient Selection; Patient-Focused Outcomes; Patients; Primary Neoplasm; Prognosis; Provider; Public Health; Quality of life; RNA; Radical Cystectomy; Recurrence; Recurrent disease; Recurrent tumor; Relapse; Research; Resistance; Selection for Treatments; Southwest Oncology Group; Testing; Transurethral Resection; Tumor Markers; Validation; base; cancer cell; cancer therapy; chemoradiation; clinical biomarkers; clinical development; cohort; follow-up; innovation; liquid biopsy; molecular marker; muscle invasive bladder cancer; non-invasive monitor; novel; outcome prediction; personalized care; predict clinical outcome; predicting response; predictive marker; predictive signature; preference; preservation; rare cancer; resistance mechanism; response; therapy resistant; tool; transcriptome sequencing; treatment response; tumor

PROJECT SUMMARY/ABSTRACT Although radical cystectomy is often recommended for muscle-invasive bladder cancer (MIBC), a well-tolerated alternative called bladder-sparing trimodality therapy (TMT), consisting of chemoradiation therapy (CRT) follow- ing transurethral resection of bladder tumor (TURBT), has equivalent long-term outcomes to cystectomy while preserving the patient’s native bladder. However, 20-30% of patients treated with TMT require a salvage cystec- tomy due to recurrent disease, and there is an unmet need for molecular biomarkers to precisely identify appro- priate candidates and to monitor for recurrences after therapy. We recently developed methods for the microflu- idic isolation and molecular characterization of circulating tumor cells (CTCs) from blood, which have potential as non-invasive, serial “liquid biopsies” to predict and monitor therapeutic responses. Our long-term goal is to develop predictive molecular biomarkers that can precisely guide the individualized care of patients with bladder cancer. The overall objectives of this application are to (i) optimize CTC and tumor molecular signatures for the prediction of therapeutic responses and longitudinal monitoring of patients treated with TMT, and (ii) to elucidate molecular mechanisms of treatment resistance based on the evolution of CTC and tumor molecular profiles after CRT. Our central hypothesis is that CTC molecular signatures, in combination with tumor molecular profiles, can predict and monitor therapeutic responses after bladder preservation therapy in patients with MIBC. The rationale for this project is that the development of molecular biomarkers will enable the tailored selection of therapy and accurate monitoring of treatment response for MIBC patients. The central hypothesis will be tested by pursuing three specific aims: 1) Identify pretreatment CTC molecular signatures that, combined with tumor molecular profiles, correlate with prognosis after TMT; 2) Identify CTC molecular signatures to monitor for early detection of recurrence after TMT; and 3) Evaluate dynamic changes in CTC and tumor molecular profiles before and after TMT to elucidate mechanisms of therapeutic resistance. In the first aim, we will optimize pretreatment CTC and tumor predictive signatures in MIBC patients undergoing TMT, followed by validation in MIBC patients enrolled in the SWOG/NRG 1806 clinical trial. In the second aim, we will optimize a CTC RNA signature for early detection of recurrence after TMT in a cohort of MIBC patients, followed by validation in patients enrolled in SWOG/NRG 1806. In the third aim, we will analyze CTC and tumor transcriptional profiles collected longitudinally from TMT patients who develop recurrent disease to identify molecular signatures associated with therapeutic resistance. The research proposed in this application is innovative because it will develop novel molecular assays based on the microfluidic isolation and RNA expression profiling of CTCs in bladder cancer patients. The proposed re- search is significant because it will yield clinically useful biomarkers for the precise selection of patients appro- priate for bladder-sparing TMT and the non-invasive monitoring of these patients, while also advancing our un- derstanding of molecular determinants of response and resistance to CRT in bladder cancer.

项目概要/摘要 虽然根治性膀胱切除术通常被推荐用于治疗肌层浸润性膀胱癌 (MIBC)，但一种耐受性良好的方法 另一种称为保留膀胱三联疗法（TMT）的替代方案，包括放化疗（CRT） 经尿道膀胱肿瘤切除术 (TURBT) 与膀胱切除术具有相同的长期结果 然而，20-30% 接受 TMT 治疗的患者需要挽救性膀胱切除术。 由于复发性疾病而造成的损伤，并且对分子生物标记物的需求尚未得到满足，以精确识别合适的 我们最近开发了微流感方法。 从血液中分离和分子表征循环肿瘤细胞（CTC），具有潜力 作为非侵入性、连续的“液体活检”来预测和监测治疗反应。 开发预测性分子生物标志物，可以精确指导膀胱患者的个体化护理 该应用的总体目标是 (i) 优化 CTC 和肿瘤分子特征。 预测 TMT 治疗患者的治疗反应和纵向监测，以及 (ii) 阐明 基于 CTC 和肿瘤分子谱的演变的治疗耐药的分子机制 CRT。我们的中心假设是，CTC 分子特征与肿瘤分子谱相结合，可以 预测和监测 MIBC 患者膀胱保留治疗后的治疗反应。 对于这个项目来说，分子生物标志物的开发将使治疗和治疗的定制选择成为可能。 准确监测 MIBC 患者的治疗反应 将通过追求来检验中心假设。 三个具体目标：1) 识别治疗前 CTC 分子特征，并与肿瘤分子相结合 2) 识别 CTC 分子特征以监测早期检测 TMT 后复发的情况；3) 评估前后 CTC 和肿瘤分子谱的动态变化 TMT 阐明治疗耐药机制 第一个目标是优化预处理 CTC 和 接受 TMT 的 MIBC 患者的肿瘤预测特征，然后在入组的 MIBC 患者中进行验证 在 SWOG/NRG 1806 临床试验中，我们将优化 CTC RNA 特征以进行早期检测。 在 MIBC 患者队列中进行 TMT 后复发，然后在 SWOG/NRG 入组的患者中进行验证 1806. 第三个目标，我们将分析从TMT纵向收集的CTC和肿瘤转录谱 患有复发性疾病的患者识别与治疗耐药性相关的分子特征。 本申请中提出的研究具有创新性，因为它将开发基于 膀胱癌患者 CTC 的微流体分离和 RNA 表达谱。 搜索具有重要意义，因为它将产生临床上有用的生物标志物，用于精确选择适合的患者。 专门用于保留膀胱的 TMT 和对这些患者的无创监测，同时也推进了我们的非侵入性监测。 了解膀胱癌 CRT 反应和耐药的分子决定因素。