Role of B-arrestins in bladder cancer progression and response to chemotherapy

B-抑制蛋白在膀胱癌进展和化疗反应中的作用

• 批准号: 10155427
• 负责人: Bal L Lokeshwar
• 金额: --
• 依托单位: CHARLIE NORWOOD VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155427
• 关键词: Adjuvant Chemotherapy; Archives; Arrestins; Basal Cell; Bladder; Bladder Neoplasm; Bladder Tissue; CRISPR/Cas technology; Cancer Cell Growth; Cancer Model; Cancer Patient; Cancer cell line; Cell Proliferation; Cells; Chemoresistance; Cisplatin; Clinical; Combination Drug Therapy; Complex; Databases; Disease; Disease-Free Survival; Enhancers; Epithelial Cells; Exhibits; Freezing; G-Protein-Coupled Receptors; Genes; Growth; Heterogeneity; Human; In Vitro; Incidence; Investigation; Knock-out; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Messenger RNA; Metabolism; Modeling; Molecular Profiling; Morbidity - disease rate; Muscle; Myomatous neoplasm; Neoadjuvant Therapy; Neoplasm Metastasis; Outcome; Patients; Pharmaceutical Preparations; Phenotype; Prediction of Response to Therapy; Prognostic Marker; Property; Proteins; Recurrence; Refractory; Reporting; Research; Research Personnel; Resistance; Role; Signal Transduction; Specimen; Testing; Tetrahydrouridine; The Cancer Genome Atlas; Time; Tissues; Tobacco-Associated Carcinogen; Treatment Cost; Treatment Failure; Treatment outcome; Tumor Tissue; United States; Urogenital Cancer; Veterans; Work; Xenograft Model; arrestin 1; arrestin 2; base; beta-arrestin; cancer cell; cancer diagnosis; cancer invasiveness; cancer stem cell; carcinogenesis; cell motility; chemokine receptor; chemotherapy; cytotoxicity; efficacy testing; environmental tobacco smoke exposure; gemcitabine; high risk; improved; individualized medicine; inhibitor/antagonist; male; member; molecular marker; mortality; muscle invasive bladder cancer; neoplastic cell; overexpression; patient derived xenograft model; pre-clinical; predict clinical outcome; prospective; refractory cancer; response; small hairpin RNA; stem cell biomarkers; tumor; tumor growth; tumor progression; tumor xenograft; tumorigenesis

Bladder cancer is the most expensive cancer to treat. Frequent recurrence and treatment refractoriness are the most common causes of morbidity and high cost of treatment of this disease. Males are three times more likely to develop bladder cancer. Therefore, the United States Veterans are at higher risk of developing bladder cancer. The high-grade, muscle invasive bladder cancers are difficult to treat and neoadjuvant and adjuvant chemotherapies have only modest benefits for overall survival. The investigators identified a pair of molecular markers that potentially determine response to chemotherapy, especially towards the Gemcitabine + Cisplatin chemotherapy combination. The markers β-Arrestin 1 (BARR1) and β-Arrestin 2 (BARR2) are members of the intracellular signaling complex triggered by chemokine receptors. The research group investigated muscle invasive bladder cancer tissues and found that BARR1 and BARR2 expressions are associated with treatment failure and metastasis. Further, in vitro studies using established bladder cancer cell lines showed an inverse correlation between BARR2 levels and the cancer stem cell phenotype, metastatic potential, and resistance to Gemcitabine induced cytotoxicity. Conversely, BARR1 expression correlated with metastasis and cancer stem cell properties. The principal hypothesis of this project is BARR1 and BARR2 are regulators of BC cell growth, differentiation into basal or luminal cell phenotype, and BC cell motility. BARR1 and BARR2 regulate malignant progressions, such as muscle invasion, metastasis, and resistance to chemotherapy drugs. Three specific aims are proposed: 1. To investigate the mechanism by which BARR1 and BARR2 regulate BC growth, cancer stem cell phenotype, and invasive/metastatic potential; 2. To investigate whether modulation of the levels of BARR1 and BARR2 alters the response to Gem treatment in preclinical BC models. Also, test the potential of tetrahydrouridine, an inhibitor of intracellular Gemcitabine metabolism, to sensitize chemotherapy-resistant Patient-derived bladder tumor xenografts (PDX) towards Gemcitabine; 3. To investigate the potential of BARR1 and BARR2 expression as a predictor of chemotherapy response and clinical outcome in MIBC. The investigators consider the high impact of this project on improving the prediction of treatment-response in high- grade bladder cancers as well as therapy response using a combination of a non-toxic drug and an established chemotherapy drug. The proposed studies have the potential to improve bladder cancer treatment and outcome for U.S. Veterans.

膀胱癌是最昂贵的癌症。频繁的复发和治疗耐磨性是 最常见的原因是发病率和该疾病的高度治疗成本。雄性的可能性是三倍 发展膀胱癌。因此，美国退伍军人面临开发膀胱的风险更高 癌症。高级，肌肉侵入性膀胱癌很难治疗和新辅助和调整 化学疗法对总体生存只有适中的好处。研究人员确定了一对分子 可能决定对化学疗法的反应的标记，尤其是对吉西他滨 +顺铂的标记 化学疗法组合。标记β-arrestin 1（Barr1）和β-arrestin 2（Barr2）是 趋化因子接收器触发的细胞内信号传导复合物。研究小组调查了肌肉 浸润性膀胱癌组织，发现Barr1和Barr2表达与治疗有关 失败和转移。此外，使用已建立的膀胱癌细胞系的体外研究表明逆 Barr2水平与癌症干细胞表型，转移性潜力以及对 吉西他滨诱导的细胞毒性。相反，Barr1表达与转移和癌症茎相关 细胞性质。该项目的主要假设是Barr1，Barr2是BC细胞生长的调节剂， 分化为碱性或腔细胞表型和BC细胞运动。 Barr1和Barr2调节恶性肿瘤 肌肉侵袭，转移和对化学疗法药物的耐药性等进度。三个具体 提出了目的：1。研究BARR1和BARR 2调节BC生长的机制，癌症 干细胞表型和侵入性/转移潜力； 2。调查是否调制 Barr1和Barr2改变了临床前BC模型中对GEM处理的反应。另外，测试潜力 四氢胺是一种细胞内吉西他滨代谢的抑制剂，可感知耐化学疗法 患者衍生的膀胱肿瘤异种移植物（PDX）朝着吉西他滨； 3。调查潜力 BARR1和BARR2表达是MIBC中化学疗法反应和临床结果的预测指标。这 研究人员认为该项目对改善高级治疗反应的预测的高影响 使用无毒药物和已建立的组合，叶片癌癌以及治疗反应 化学疗法药物。拟议的研究有可能改善膀胱癌治疗和 美国退伍军人的结果。