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.

膀胱癌是治疗费用最高的癌症，其原因是频繁复发和治疗难治性。 男性发病率和治疗费用高的可能性是男性的三倍。 因此，美国退伍军人患膀胱癌的风险较高。 高级别、肌肉浸润性膀胱癌很难治疗，需要新辅助和辅助治疗。 研究人员发现，化疗对总体生存只有有限的益处。 可能决定化疗反应的标志物，尤其是吉西他滨 + 顺铂 标记物 β-Arrestin 1 (BARR1) 和 β-Arrestin 2 (BARR2) 是化疗组合的成员。 研究小组研究了由趋化因子受体触发的细胞内信号复合物。 侵袭性膀胱癌组织，发现 BARR1 和 BARR2 表达与治疗相关 此外，使用已建立的膀胱癌细胞系的体外研究显示出相反的情况。 BARR2水平与癌症干细胞表型、转移潜能和耐药性之间的相关性 吉西他滨诱导离线细胞毒性，BARR1 表达与转移和癌症干细胞相关。 该项目的主要假设是 BARR1 和 BARR2 是 BC 细胞生长的调节因子， 分化为基底细胞或管腔细胞表型，BC 细胞运动性调节。 进展，例如肌肉侵袭、转移和对化疗药物的抵抗三个特定的。 提出的目标： 1. 研究 BARR1 和 BARR2 调节 BC 生长、癌症的机制 2. 研究是否调节干细胞表型和侵袭/转移潜力； BARR1 和 BARR2 改变了临床前 BC 模型对 Gem 治疗的反应。 四氢尿苷，一种细胞内吉西他滨代谢抑制剂，可提高化疗耐药性 3. 研究吉西他滨的患者来源膀胱肿瘤异种移植物（PDX）的潜力； BARR1 和 BARR2 表达作为 MIBC 化疗反应和临床结果的预测因子。 研究人员认为该项目对改善高危人群治疗反应的预测具有重大影响 膀胱癌分级以及使用无毒药物和已建立的药物组合的治疗反应 拟议的研究有可能改善膀胱癌的治疗和治疗。 美国退伍军人的结果。