Novel Biomarkers for the Clinical Management of Bladder Cancer

用于膀胱癌临床管理的新型生物标志物

• 批准号: 10659210
• 负责人: Vinata B Lokeshwar
• 金额: $ 42.98万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-13 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659210
• 关键词: Adjuvant; Benign; Biological Markers; Bladder; Bladder Neoplasm; Blinded; Cancer Patient; Chemoresistance; Chemotherapy-Oncologic Procedure; Chondroitin Sulfate Proteoglycan; Chondroitinases; Cisplatin; Clinic; Clinical; Clinical Management; Cystectomy; Cystoscopy; Cytology; Diagnosis; Diagnostic; Disease; Disease Progression; Early Diagnosis; Early Intervention; Enzyme-Linked Immunosorbent Assay; Enzymes; Evaluation; Excision; FDA approved; Family; Future; Genes; Genitourinary system; Glycosaminoglycans; Goals; Growth; Hematuria; Human; Immunohistochemistry; Infection; Invaded; Laboratories; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; Messenger RNA; Microscopic; Monitor; Morbidity - disease rate; Muscle Development; Names; Neoplasm Metastasis; Non-Invasive Detection; Outcome; Pain; Painless; Patients; Persons; Pilot Projects; Positive Test Result; Procedures; Prospective Studies; RNA Splicing; Recommendation; Recurrence; Recurrent Malignant Neoplasm; Recurrent tumor; Research Design; Resistance; Retrospective Studies; Risk; Risk Factors; Specificity; Specimen; Spottings; Symptoms; Test Result; Testing; Tissues; Urine; Urography; Urothelial Cell; Validation; Variant; accurate diagnosis; cancer diagnosis; cancer recurrence; chemotherapy; clinical practice; cost; design; detrusor muscle; efficacy testing; follow-up; gemcitabine; improved; individualized medicine; longitudinal, prospective study; member; mortality; muscle invasive bladder cancer; noninvasive diagnosis; novel; novel marker; predict clinical outcome; predicting response; prognostic; public health relevance; rate of change; response; tissue biomarkers; treatment response; tumor; tumor growth; urologic; validation studies

ABSTRACT: The current clinical practice of invasive diagnostic workup, frequent recurrence following bladder tumor resection, and high propensity of muscle invasive bladder cancer (MIBCa) for metastasis, contribute to the significant morbidity and mortality associated with bladder cancer (BCa); one of the costliest cancer to manage clinically. Painless hematuria is the common presenting symptom among BCa patients. However, only 15-25% of patients with visible hematuria and about 10% of the patients with microscopic hematuria actually have BCa. Patients presenting with hematuria undergo urological workup that involves cystoscopy and CT- urography. Cystoscopy is invasive and uncomfortable and both procedures associate with considerable risk for morbidity and are costly. Frequent BCa recurrence requires surveillance by cystoscopy every 3 to 6 months. Non-invasive biomarkers, including urine cytology, can reduce the invasive and costly workup among patients with hematuria or for those under surveillance for monitoring BCa recurrence. However, existing biomarkers are not used in clinic due to their sub-optimal efficacy and/or high false-positive rate. Further, biomarkers are not used for predicting clinical outcome in terms of metastasis or treatment response after a bladder removal surgery. In pilot studies, two new non-invasive tests based on a novel member of a glycosaminoglycan family, showed high accuracy to detect BCa, for non-invasively evaluating its grade and for early detection of BCa recurrence. Biomarker levels in BCa tissues correlated with clinical outcome. This project is designed to evaluate a hypothesis that this two urine tests can accurately diagnose BCa and non-invasively evaluate its grade among patients needing urological workup for hematuria, or to monitor BCa recurrence. Furthermore the tissue-based biomarkers accurately predict clinical outcome. The efficacy of both urine tests will be evaluated for BCa diagnosis and for evaluation of its grade among patients undergoing urological workup for hematuria (Aim 1). Efficacy of these urine tests will be compared to cystoscopy findings in patients under surveillance for monitoring BCa recurrence. The tests’ findings will also be evaluated for predicting future recurrence (Aim 2). The biomarkers’ expression in BCa tissues will be examined for predicting the development of MIBCa, metastasis and overall clinical outcome (Aim3). Impact: The study may result in two validated urine tests for non-invasively and accurately detecting BCa with grade evaluation as an added benefit. This could substantially reduce the number of patients undergoing urological workup for hematuria or surveillance cystoscopies for monitoring BCa recurrence. Tissue biomarkers, if found to be accurate prognosticators, could reduce unnecessary invasive bladder re-resections for MIBCa, and aid in early intervention and individualized treatment for patients with advanced BCa. Overall, if efficacious, these biomarkers could reduce BCa-related morbidity, and costs, while improving clinical outcome by early predictions.

摘要：目前侵入性诊断检查的临床实践，膀胱术后复发频繁 肿瘤切除和肌层浸润性膀胱癌 (MIBCa) 的高转移倾向有助于 与膀胱癌（BCa）相关的显着发病率和死亡率；膀胱癌是治疗成本最高的癌症之一； 临床上，无痛性血尿是 BCa 患者常见的症状。 15-25%的患者出现肉眼血尿，约10%的患者实际出现镜下血尿 患有 BCa 的患者需接受泌尿科检查，包括膀胱镜检查和 CT 检查。 膀胱镜检查是侵入性的且不舒服，并且这两种手术都存在相当大的风险。 BCa 复发需要每 3 至 6 个月进行一次膀胱镜检查。 非侵入性生物标志物，包括尿细胞学检查，可以减少患者的侵入性且昂贵的检查 患有血尿或正在接受 BCa 复发监测的患者。 由于其疗效欠佳和/或假阳性率较高，因此未在临床中使用。此外，生物标志物也不是。 用于预测膀胱切除手术后转移或治疗反应方面的临床结果。 在试点研究中，两项新的非侵入性测试基于糖胺聚糖家族的新成员， 在检测 BCa、非侵入性评估其等级以及早期检测 BCa 方面表现出很高的准确性 BCa 组织中的生物标志物水平与临床结果相关。 假设这两项尿液测试可以准确诊断 BCa 并无创地评估其​​等级 需要针对血尿进行泌尿科检查或监测 BCa 复发的患者。 生物标志物准确预测临床结果。 将评估这两项尿液测试的功效以进行 BCa 诊断及其等级评估 接受泌尿科血尿检查的患者（目标 1）将与这些尿液检查的效果进行比较。 接受监测 BCa 复发的患者的膀胱镜检查结果也将被纳入。 评估预测未来复发（目标 2）。 用于预测 MIBCa 的发展、转移和总体临床结果 (Aim3)。 影响：该研究可能会产生两项经过验证的尿液检测，以非侵入性且准确地检测 BCa 等级评估作为一项额外的好处，可以大大减少接受治疗的患者数量。 泌尿系统血尿检查或膀胱镜检查以监测组织生物标志物， 如果被发现是准确的预测因素，可以减少 MIBCa 不必要的侵入性膀胱再切除术， 并帮助晚期 BCa 患者进行早期干预和个体化治疗。总体而言，如果有效的话， 这些生物标志物可以降低BCa相关的发病率和成本，同时通过早期治疗改善临床结果 预测。

项目成果

A chemokine/chemokine receptor signature potentially predicts clinical outcome in colorectal cancer patients.

• DOI: 10.3233/cbm-190210
• 发表时间: 2019
• 期刊: Cancer biomarkers : section A of Disease markers
• 作者: Mitchell A;Hasanali SL;Morera DS;Baskar R;Wang X;Khan R;Talukder A;Li CS;Manoharan M;Jordan AR;Wang J;Bollag RJ;Singh N;Albo D;Ghosh S;Lokeshwar VB
• 通讯作者: Lokeshwar VB

Clinical Parameters Outperform Molecular Subtypes for Predicting Outcome in Bladder Cancer: Results from Multiple Cohorts, Including TCGA.

• DOI: 10.1097/ju.0000000000000351
• 发表时间: 2020-01
• 期刊: The Journal of urology
• 作者: Morera DS;Hasanali SL;Belew D;Ghosh S;Klaassen Z;Jordan AR;Wang J;Terris MK;Bollag RJ;Merseburger AS;Stenzl A;Soloway MS;Lokeshwar VB
• 通讯作者: Lokeshwar VB

Targeting hyaluronic acid synthase-3 (HAS3) for the treatment of advanced renal cell carcinoma.

• DOI: 10.1186/s12935-022-02818-1
• 发表时间: 2022-12-29
• 期刊: Cancer cell international
• 影响因子: 5.8

Diagnostic utility of axial imaging in the evaluation of hematuria: A systematic review and critical appraisal of the literature.

轴位成像在血尿评估中的诊断效用：对文献的系统回顾和批判性评价。

• DOI: 10.5489/cuaj.6522
• 发表时间: 2021
• 期刊: Canadian Urological Association journal = Journal de l'Association des urologues du Canada
• 作者: Wallis,ChristopherJD;Sayyid,RashidK;Manyevitch,Roni;Perlis,Nathan;Lokeshwar,VinataB;Fleshner,NeilE;Terris,MarthaK;Nielsen,MatthewE;Klaassen,Zachary
• 通讯作者: Klaassen,Zachary

Molecular Oncology of Bladder Cancer from Inception to Modern Perspective.

• DOI: 10.3390/cancers14112578
• 发表时间: 2022-05-24
• 期刊: Cancers
• 影响因子: 5.2