A Multiplex Protein Biomarker-Based Immunoassay for the Early Detection of Bladder Cancer and its Implications in Tumor Biology

用于膀胱癌早期检测的多重蛋白质生物标志物免疫测定及其在肿瘤生物学中的意义

• 批准号: 10591629
• 负责人: Hideki Furuya
• 金额: $ 37.63万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-07 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591629
• 关键词: Address; American; Animal Model; Biological Assay; Biological Markers; Bladder; Bladder Neoplasm; Blood; Cancer Diagnostics; Cancer Model; Cancer Patient; Carcinogens; Cessation of life; Clinic; Clinical; Cytometry; Data; Death Rate; Diagnosis; Disease; Early Diagnosis; Early identification; Educational workshop; Epithelium; Evaluation; Exposure to; Future; Hematuria; Human; IL8 gene; Image; Immunoassay; Individual; Link; Location; MMP9 gene; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Messenger RNA; Methodology; Methods; Modality; Mus; Non-Invasive Detection; Outcome; Patients; Phase; Pilot Projects; Plasminogen Activator Inhibitor 1; Predictive Value; Prospective Studies; Recording of previous events; Research; Risk; Rodent Model; Role; Sampling; Smoker; Specificity; Survival Rate; Technology; Testing; Time; Tissues; Tumor Biology; Urine; VEGFA gene; Validation; cancer biomarkers; cancer diagnosis; candidate marker; carcinogenesis; clinical application; clinical development; clinical diagnosis; clinically relevant; cohort; combat; diagnostic signature; high risk; high risk population; improved; innovation; longitudinal, prospective study; men; novel; novel marker; overexpression; prospective; protein biomarkers; research clinical testing; single-cell RNA sequencing; stromelysin 2; surveillance study; tumor; tumor initiation; tumor microenvironment; tumorigenesis; urinary

Project Summary/Abstract Background Over 83,000 Americans will be diagnosed with bladder cancer in 2021 with over 17,000 dying of the disease during this period. Unfortunately, both the absolute numbers of cases and deaths from bladder cancer have increased by 57 and 41%, respectively, since 2000. When detected early (i.e., NMIBC or stage 1), the 5-yr survival rate is >90%, compared to a significant reduction in survival if the disease is noted to be MIBC (stage 2; 50% 5-yr survival) or metastatic (stages 3 and 4; <20% 5-yr survival). Thus, the prevailing idea is that early detection of bladder cancer in high risk individuals (i.e., individuals exposed to certain carcinogens) will likely be the best modality to address advanced bladder cancer’s dismal outcomes. Currently, the evaluation of at risk individuals remains a challenge, and as such, there are no modalities available to effectively screen this high risk population. Previously, we have a) identified a bladder cancer-associated diagnostic “signature” comprised of 10 biomarkers, b) developed a multiplex immunoassay to query the “signature” in voided urine samples and c) performed analytical validation of the multiplex immunoassay. Using the multiplex immunoassay, we have generated encouraging preliminary data from a cohort of 362 subjects (46 cancers) (AUC 0.95; sensitivity 0.93, specificity 0.93, positive predictive value 0.65 and negative predictive value 0.99). Thus, for the first time, we possess a robust assay that can be used to non-invasively detect bladder cancer. Utilizing this assay in our ongoing prospective study surveilling patients with a history of bladder cancer, we have noted an elevation of our ‘signature’ as early as 18 months prior to the clinical diagnosis of cancer and an actual positive multiplex immunoassay in all cancer patients 12 months prior to the clinical diagnosis of cancer. Furthermore, we have evidence that 9 of our 10 biomarkers within the “signature” are expressed in relevant carcinogen induced mouse bladder cancer model. Hypothesis: A bladder cancer-associated signature exists that can be leveraged to indicate the presence of bladder cancer from a single voided urine sample months to years prior to the clinical presentation and diagnosis of bladder cancer. Specific Aims: 1) To perform a pilot study to evaluate the multiplex immunoassay’s ability to early detect bladder cancer and 2) To use a relevant carcinogen induced mouse bladder cancer model to identify early changes within the tumor microenvironment which could serve as biomarkers candidates for testing in human samples. Significance This research will open the door for improving on the non-invasive methods for the early detection of bladder cancer, and as such, it will have a marked impact on patient survival. Methodology We will conduct a prospective pilot study (n=150) to demonstrate the feasibility of identifying, following and testing high risk individuals for bladder cancer. Then utilizing a relevant carcinogen induced mouse bladder cancer model, we will study the spatial and temporal association of our “signature” and link it to key changes within the tumor microenvironment, identifying novel biomarkers for future clinical development. Expected Results There exists an unmet clinical need for reliable biomarkers to early detect bladder cancer when its more treatable with improved survival rates.

项目摘要/摘要 2021年，将被诊断出83,000多名美国人患有膀胱癌的背景 该疾病在此期间。不幸的是，刀片的案件和死亡的绝对数量 自2000年以来，癌症分别增加了57％和41％。 5年的生存率> 90％，相比之下，如果发现该疾病为MIBC，则存活率显着降低 （第2期； 50％5年生存）或转移性（第3和4阶段； <20％5年生存）。那是普遍的想法 早期发现高风险个体（即暴露于某些致癌物的个体）的膀胱癌的早期发现将 可能是解决高级膀胱癌惨淡结果的最佳方式。目前，评估 处于风险的人仍然是一个挑战，因此，没有任何方式可以有效筛选 高风险人群。以前，我们有a）确定了与膀胱相关的诊断“签名” 由10个生物标志物组成，b）开发了一个多重免疫测定法，以查询变白的“签名” 样品和c）对多重免疫测定进行了分析验证。使用多重免疫测定， 我们从362名受试者（46个癌症）（AUC 0.95）组中产生了令人鼓舞的初步数据。 灵敏度0.93，特异性0.93，正预测值0.65和负预测值0.99）。那，为 第一次，我们拥有可用于非侵入性检测膀胱癌的强大测定法。利用这个 在我们正在进行的前瞻性研究中监视患有膀胱癌病史的患者的测定，我们注意到 早在癌症临床诊断之前的18个月前，我们的“签名”提升和实际阳性 在癌症临床诊断前12个月，所有癌症患者的多重免疫测定法。此外， 我们有证据表明，“签名”中的10个生物标志物中有9个在相关的致癌物中表达 小鼠膀胱癌模型。假设：存在可以利用的膀胱癌相关的签名 指示临床前几个月至数年的单个无效的尿液样本中存在膀胱癌 膀胱癌的表现和诊断。具体目的：1）进行试点研究以评估 多重免疫测定能够早期检测膀胱癌的能力，2）使用相关致癌 小鼠膀胱癌模型以识别肿瘤微环境内的早期变化，可以用作 生物标志物在人类样品中进行测试的候选者。意义这项研究将为 改善了早期检测到膀胱癌的非侵入性方法，因此，它将具有 对患者生存的明显影响。方法论我们将进行一项前瞻性试验研究（n = 150） 证明识别，跟随和测试高风险个体的膀胱癌的可行性。然后 使用相关的致癌小鼠膀胱癌模型，我们将研究空间和临时性 我们的“签名”的关联，并将其与肿瘤微环境内的关键变化联系起来，识别出新颖 未来临床开发的生物标志物。预期结果存在未满足的可靠临床需求 当生物标志物以提高生存率而更可治疗的生物标志物检测到膀胱癌。