MULTIPLEXED PROTEIN BIOMARKER-BASED ASSAY FOR THE DETECTION OF BLADDER CANCER

用于检测膀胱癌的多重蛋白质生物标志物检测

• 批准号: 10672214
• 负责人: Charles J Rosser
• 金额: $ 65.13万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672214
• 关键词: Adjuvant; Adjuvant Therapy; Age; Algorithms; BCG Live; Biological Assay; Biological Markers; Bladder; Blood; Cancer Detection; Cancer Patient; Caring; Clinic; Clinical; Cohort Studies; Cost Analysis; Cost Savings; Cost utility; Costs and Benefits; Cystectomy; Cystoscopy; Cytology; Data; Diagnosis; Disease; Effectiveness; Ensure; Evaluation; Excision; Funding; Gender; General Population; Guidelines; Health Care Costs; Hematuria; Image; Immunoassay; Institution; Invasive Lesion; Laboratories; Life; Malignant neoplasm of urinary bladder; Manuscripts; Measures; Medicine; Methodology; Microscopic; Molecular Profiling; Muscle; Newly Diagnosed; Parents; Patient Care; Patients; Performance; Prediction of Response to Therapy; Predictive Value; Prospective cohort; Publishing; Recommendation; Recording of previous events; Recurrence; Research; Residual Neoplasm; Retrospective cohort; Risk; Sampling; Schedule; Specificity; Survival Rate; Technology; Technology Transfer; Testing; Time; Tobacco; Translating; Translations; Transurethral Resection; Tumor stage; Urine; Validation; Weight; cancer biomarkers; cancer diagnosis; clinically relevant; cohort; cost effective; cost effectiveness; detection assay; detection method; diagnostic assay; diagnostic signature; high risk; improved; intravesical; markov model; multiplex assay; muscle invasive bladder cancer; patient response; patient stratification; predicting response; predictive modeling; preservation; prospective; protein biomarkers; response; risk stratification; treatment response; tumor; tumorigenesis; urinary

Project Summary/Abstract Background Microscopic hematuria (blood in urine) may occur in up to 10% of the general population and results in costly evaluation to ensure it is of no consequence, i.e., no bladder cancer (BCa) is present since hematuria is typically the initial sign of BCa. Furthermore, 75% of patients with newly diagnosed BCa have non- muscle-invasive disease (NMIBC), which has a very high recurrence rate (>70%). Because of this, it is recommended that the patients have adjuvant intravesical bacillus Calmette-Guerin (BCG) instillation to reduce this risk. Despite BCG treatment, up to 50% of patients fail to respond and 20% progress to muscle invasive bladder cancer (MIBC) mandating more radical treatment (i.e., cystectomy - removal of the urinary bladder). Moreover, the delay in radical treatment can negatively impact survival rates, hence, a test that could predict treatment response to intravesical BCG, ensuring the right patient, gets the right treatment at the right time is urgently required. To date, no such test is available. There exists an unmet clinical need for reliable biomarkers to a) ‘rule out’ which patients with microscopic hematuria do not require further evaluation and b) predict which patients will respond to BCG. Hypothesis Our central hypothesis is that a molecular profile exists that is specifically associated with BCa that a) can be utilized to indicate the presence of BCa in non-invasively obtained urine samples and b) can be utilized to predict response to BCG. This hypothesis will be tested by completing the following Specific Aims: 1) To validate the multiplex immunoassay for BCa detection in subjects presenting with microscopic hematuria, 2) To evaluate the cost benefit, cost utility and cost effectiveness of the multiplex immunoassay in subjects with hematuria and a history of BCa on tumor surveillance and 3) To validate prospectively the urine-based multiplex immunoassay to predict BCG response in subjects with intermediate/high risk NMIBC. Significance This research will open the door for improving on the non-invasive methods for detecting BCa and predicting treatment response as such it will have a marked impact on patient care. Methodology Our group has developed and tested a multiplex immunoassay towards a BCa signature with extremely encouraging results in subjects evaluated for gross hematuria and a history of BCa on tumor surveillance. In the current proposal, we now seek to test the multiplex assay in two additional independent cohorts: intermediate/high-risk patients (AUA microscopic hematuria guidelines 2020) presenting with microscopic hematuria for early BCa detection and patients with intermediate/high risk NMIBC treated with intravesical BCG to predict treatment response. Furthermore, we will generate Markov models and using data collected from the parent R01 to assess cost benefit, cost utility and cost effectiveness of the multiplex immunoassay. Expected Results The validation of the multiplex immunoassay will reduce the need to subject large numbers of patients who do not have BCa to frequent, uncomfortable and expensive cystoscopic examinations. Specifically, we would anticipate a reduction in the number of cystoscopies/year by 500,000, which would translate into cost savings of $225 million/year.

项目概要/摘要 背景 高达 10% 的普通人群可能会出现镜下血尿（尿中带血）， 导致昂贵的评估以确保其不会产生任何后果，即自那时以来不存在膀胱癌（BCa） 血尿通常是 BCa 的最初症状。此外，75% 的新诊断 BCa 患者患有非 BCa。 肌肉侵袭性疾病（NMIBC），其复发率非常高（>70%）。 建议患者进行膀胱内卡介苗（BCG）辅助滴注以减少 尽管进行了 BCG 治疗，仍有高达 50% 的患者没有反应，20% 的患者进展为肌肉侵袭性。 膀胱癌（MIBC）需要更彻底的治疗（即膀胱切除术 - 切除膀胱）。 此外，根治性治疗的延迟会对生存率产生负面影响，因此，一项可以预测的测试 对膀胱内卡介苗的治疗反应，确保正确的患者在正确的时间得到正确的治疗 迄今为止，尚无可用的可靠生物标志物的临床需求。 a) “排除”哪些患有镜下血尿的患者不需要进一步评估；b) 预测哪些患者 假设我们的中心假设是存在一种分子特征： 与 BCa 特别相关，a) 可用于非侵入性地指示 BCa 的存在 获得的尿液样本和 b) 可用于预测对 BCG 的反应 该假设将由以下人员进行检验。 完成以下具体目标： 1) 验证用于 BCa 检测的多重免疫分析 出现镜下血尿的受试者，2) 评估成本效益、成本效用和成本 多重免疫测定对有血尿和 BCa 病史的受试者对肿瘤的有效性 监测和 3) 前瞻性验证基于尿液的多重免疫分析来预测 BCG 反应 在具有中/高风险 NMIBC 的受试者中 意义 这项研究将为改进打开大门。 用于检测 BCa 和预测治疗反应的非侵入性方法，因此它将具有 对患者护理产生显着影响 我们的团队开发并测试了多重免疫分析。 BCa 标志在评估肉眼血尿的受试者中取得了极其令人鼓舞的结果 BCa 在肿瘤监测中的历史 在当前的提案中，我们现在寻求在两种情况下测试多重检测。 其他独立队列：中危/高危患者（AUA 镜下血尿指南 2020 年） 出现镜下血尿以进行早期 BCa 检测以及中/高风险 NMIBC 患者 此外，我们将生成马尔可夫模型并用膀胱内 BCG 进行治疗以预测治疗反应。 使用从母公司 R01 收集的数据来评估成本效益、成本效用和成本效益 多重免疫测定的预期结果多重免疫测定的验证将减少需求。 使大量没有 BCa 的患者遭受频繁、不舒服和昂贵的治疗 具体来说，我们预计每年的膀胱镜检查次数将减少 500,000，这将意味着每年节省 2.25 亿美元的成本。

项目成果

A Nomogram Derived by Combination of Demographic and Biomarker Data Improves the Noninvasive Evaluation of Patients at Risk for Bladder Cancer.

• DOI: 10.1158/1055-9965.epi-16-0260
• 发表时间: 2016-09
• 期刊: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
• 作者: Huang S;Kou L;Furuya H;Yu C;Goodison S;Kattan MW;Garmire L;Rosser CJ
• 通讯作者: Rosser CJ

Meta-analysis of a 10-plex urine-based biomarker assay for the detection of bladder cancer.

• DOI: 10.18632/oncotarget.23872
• 发表时间: 2018-01-23
• 期刊: Oncotarget
• 作者: Masuda, Norihiko;Ogawa, Osamu;Kobayashi, Takashi
• 通讯作者: Kobayashi, Takashi

Diagnostic performance of Oncuria™, a urinalysis test for bladder cancer.

• DOI: 10.1186/s12967-021-02796-4
• 发表时间: 2021-04-06
• 期刊: Journal of translational medicine
• 影响因子: 7.4
• 作者: Hirasawa Y;Pagano I;Chen R;Sun Y;Dai Y;Gupta A;Tikhonenkov S;Goodison S;Rosser CJ;Furuya H
• 通讯作者: Furuya H

Association of MMP-2, RB and PAI-1 with decreased recurrence-free survival and overall survival in bladder cancer patients.

• DOI: 10.18632/oncotarget.20686
• 发表时间: 2017-11-21
• 期刊: Oncotarget
• 作者: Chan OTM;Furuya H;Pagano I;Shimizu Y;Hokutan K;Dyrskjøt L;Jensen JB;Malmstrom PU;Segersten U;Janku F;Rosser CJ
• 通讯作者: Rosser CJ

Repeat Transurethral Resection of Muscle-invasive Bladder Cancer Prior to Radical Cystectomy Is Prognostic but Not Therapeutic. Letter.

在根治性膀胱切除术之前重复经尿道切除肌层浸润性膀胱癌可以预测预后，但不能起到治疗作用。

• DOI: 10.1097/ju.0000000000003362
• 发表时间: 2023
• 期刊: The Journal of urology
• 作者: Castaneda,PerisR;Ahdoot,Michael;Rosser,CharlesJ
• 通讯作者: Rosser,CharlesJ