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

膀胱癌是治疗费用最高的癌症。复发频繁和治疗难治是 最常见的致病原因和高昂的治疗费用。男性是男性的三倍 患上膀胱癌。因此，美国退伍军人患膀胱癌的风险更高 癌症。高级别、肌肉浸润性膀胱癌难于治疗，新辅助和辅助治疗。 化疗对总体存活率的益处不大。调查人员发现了一对分子 可能决定化疗反应的标志物，特别是对吉西他滨顺铂的反应 化疗组合。标记β-arrestin 1(BARR1)和β-arrestin 2(BARR2)是 趋化因子受体触发的细胞内信号复合体。研究小组对肌肉进行了调查 发现BARR1和BARR2的表达与治疗有关 失败和转移。此外，使用已建立的膀胱癌细胞系进行的体外研究显示情况相反 BARR2水平与肿瘤干细胞表型、转移潜能和耐药性的相关性 吉西他滨具有细胞毒性作用。相反，BARR1的表达与肿瘤转移和肿瘤干细胞有关 单元格属性。该项目的主要假设是BARR1和BARR2是BC细胞生长的调节因子， 分化为基细胞或腔细胞表型，以及BC细胞的运动。BARR1和BARR2调控恶性病变 进展，如肌肉侵袭、转移和对化疗药物的耐药性。三个具体的 目的：1.探讨BARR1和BARR2调控BC生长、肿瘤的机制 干细胞表型和侵袭/转移潜能；2.研究 在临床前BC模型中，BARR1和BARR2改变对Gem治疗的反应。此外，还要测试一下 细胞内吉西他滨代谢抑制剂四氢尿苷增敏化疗耐药 吉西他滨患者源性膀胱肿瘤异种移植(PDX)的实验研究 BARR1和BARR2的表达可预测MIBC的化疗疗效和临床预后。这个 研究人员认为，该项目对提高对高危患者治疗反应的预测有很大影响。 膀胱癌分级以及使用无毒药物和已建立的联合应用的治疗反应 化疗药物。拟议的研究有可能改善膀胱癌的治疗和 美国退伍军人的结果。

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.